Role of inflammation in the progression of diabetic kidney disease
0 Abstract
Diabetic kidney disease (DKD) is a global health burden and the leading cause of end-stage renal disease. Its clinical management focuses on controlling hyperglycemia, hypertension, and hyperlipidemia. While the progression of DKD can be slowed with intervention, it cannot be stopped or reversed yet. The pathogenesis of DKD is complex, with an interplay of numerous signaling pathways, and research continues to decipher the players and their role, be it beneficial or pathogenic. Inflammation is an essential defense of our bodies against internal or external insults. The injuries that trigger inflammation range from pathogenic infections and wounds to dysregulated metabolism. Inflammation is helpful only if it is controlled and subsides after it has helped defend the individual against the insult. Uncontrolled or chronic inflammation is recognized as a contributor to numerous chronic diseases. Dysregulated inflammation plays a role in multiple aspects of DKD: glomerular hyperfiltration, mesangial expansion, podocyte injury, tubular injury, basement membrane thickening, fibrosis, and scarring. Since inflammation plays an integral role in the progression of DKD, targeting it for therapy is also reasonable. There is a growing trend of targeting inflammation as a therapeutic approach, with new targets being discovered and drugs evaluated every year. The exponential increase in literature necessitates a comprehensive summary of current information, hence this review.
Keywords
INTRODUCTION
The International Diabetes Federation estimates that 537 million adults have diabetes, and ~40% of them develop DKD[1,2]. New cases of chronic kidney disease (CKD) in patients with T2DM or type-2 DKD increased by 74% between 1990 and 2017[2]. DKD is associated with a higher risk of cardiovascular events, kidney failure, and premature mortality[2-4]. The global health burden of DKD is expected to worsen, necessitating urgent action in policy-making and research. Diabetes prevention and control remain the primary goals of preventing DKD. Clinical management focuses on managing hyperglycemia, hypertension, and hyperlipidemia to slow progression[4]. Complete stoppage or reversal remains a goal.
Inflammation is an essential defense of our bodies against internal or external injury. Pattern recognition receptors (PRRs) sense pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs) and induce inflammatory signaling cascades, producing cytokines. These molecules act in an autocrine manner to enhance inflammatory signaling and in a paracrine manner to recruit and activate immune cells like macrophages, lymphocytes, and dendritic cells. This is followed by immune cell-mediated clearance of pathogens or damaged tissue. The final step of inflammation is its resolution, which re-establishes homeostasis[5]. The persistence of inflammatory inducers or inefficient resolution results in chronic inflammation causing oxidative stress (OS) and mitochondrial dysfunction (e.g., increased free radicals, advanced glycation endproducts (AGEs), and oxidized lipoproteins), further perpetuating inflammation in a feed-forward loop[6].
Although not the initiator, low-grade inflammation occurs in diabetes before the onset of DKD[7,8]. A chronic inflammatory state in a prediabetic individual can predict T2DM development[9]. Inflammation progresses alongside DKD, evidenced by the infiltration of immune cells in kidney biopsies and association studies showing the upregulation of inflammatory pathways[10-14]. Single-cell transcriptomic analyses corroborate immune-cell infiltration and upregulation of inflammatory pathways[15-17]. A chronic inflammatory insult to the kidney contributes to various structural and functional changes in DKD[18]. The kidney risk inflammatory signature (KRIS) comprising 17 circulating inflammatory proteins of a non-renal source relates to a higher risk of end-stage renal disease (ESRD) in patients with diabetes[19]. Other serum and urinary markers of renal and systemic inflammation correlate well with renal decline in T1DM- and T2DM-DKD[20,21], and they might predict the presence and prognosis of DKD[22].
We aim to review recent advances in research that help us better understand the role of inflammation in DKD. We describe how inflammation is intertwined in its pathogenesis and progression, followed by a review of the inflammatory pathways and players involved. Finally, we reflect on their therapeutic potential and future possibilities.
INFLAMMATION IN THE PATHOGENESIS OF DKD
DKD is a clinical diagnosis of persistent albuminuria (urinary albumin excretion (UAE)
DKD pathogenesis is multifactorial [Figure 1]. Hyperglycemia is the most well-researched and obvious trigger for diabetes and its associated complications. However, other metabolic derangements and hemodynamic abnormalities also contribute. Metabolic factors, like excess fatty acids, AGEs, and OS, activate inflammatory pathways[25,26]. Fructose exposure reduced lymphocyte subpopulations, increased DNA damage, and dysregulated immune-related genes, including mitogen-activated protein kinase 8 (MAPK8 or JNK1) and leukocyte-specific transcript 1 (LST1)[27]. A sugar-rich diet triggers a pro-inflammatory response via altering the gut microbiome and Toll-like receptor 4 (TLR4) signaling[28]. Superoxide and presumably other ROS activate TLR4 signaling and neutrophil NADPH oxidase (NOX) to form neutrophil extracellular traps (NETs)[29]. NETs are networks of extracellular fibers, mainly composed of neutrophil DNA, which trap and kill pathogens by engulfing them, producing antimicrobials, and saving host cells from damage. NETs increase in patients and murine models of DKD and correlate with DKD severity[30]. In sterile inflammation, NETs probably form to counter cell death and OS.
Figure 1. Pathogenesis and progression of DKD. The upper panel outlines the primary triggers of DKD in the diabetic milieu, viz. hyperglycemia, dyslipidemia, and microinflammation (a chronic low-grade inflammatory state can predict and predispose an individual to diabetes and DKD). These triggers induce several metabolic, hemodynamic, and inflammatory factors. The interconnected factors cause intracellular changes followed by progressively detrimental alterations to the renal architecture, leading to fibrosis, scarring, and functional decline, ultimately resulting in renal failure. The lower panel recounts pathophysiological changes with the progression of DKD. AGEs: Advanced glycation endproducts; CCL: CC motif chemokine ligand; CTGF: connective tissue growth factor; DKD: diabetic kidney disease; EMT: epithelial-to-mesenchymal transition; EndMT: endothelial-to-mesenchymal transition; GFR: glomerular filtration rate; ICAM: intercellular adhesion molecule; IL: interleukin; NO: nitric oxide; NOX: NADPH oxidase; PDGF: platelet-derived growth factor; PKC: protein kinase C; RAAS: renin-angiotensin-aldosterone system; ROS: reactive oxygen species; TGF: transforming growth factor; TNF: tumor necrosis factor; VCAM: vascular cell adhesion molecule; VEGF: vascular endothelial growth factor.
Similarly, hemodynamic abnormalities, such as hypertension-induced shear stress, microvascular changes resulting in hyperperfusion or hypoxia, and renin-angiotensin-aldosterone system (RAAS) activation, contribute to the complex network of pathogenetic events in the kidney, including an increase in growth factors, vasoactive hormones, and most relevant to this review, pro-inflammatory cytokines and chemokines[31,32].
An inflammatory response has the following contributors: inducers (infection, tissue damage, pathology), sensors (cells expressing PRRs), mediators (cytokines, chemokines), and the tissues that are affected[5]. In the context of the diabetic kidney, the inducers are hyperglycemia, AGEs, ROS, and DAMPs. All renal cell types express PRRs to sense pathological changes in their vicinity and act as inflammatory sensors. The mediators are not inherently different in the kidneys. The target tissues are the damaged cells and regions in the kidney that require repair. Next, we review the different spatiotemporal roles of inflammation in the progression of DKD pathology.
Glomerular inflammation
Damage to the renal glomeruli is considered one of the first events in DKD development, including GBM thickening, mesangial expansion, podocyte loss, and glomerulosclerosis. Podocytes and endothelial cells are responsible for maintaining the GBM, its charge barrier, and the shape and integrity of the glomerular capillary loop, which are all compromised in the diabetic glomerulus[32]. The diabetic milieu with numerous inflammatory inducers triggers the release of pro-inflammatory cytokines and activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) with a pyrin domain 3 (NLRP3) inflammasome in podocytes[33,34]. Induced podocyte-derived cytokines, like TNF-α, mediate monocyte differentiation and macrophage recruitment, contributing to glomerular injury and proteinuria[34]. Levels of serum amyloid A (SAA), a potent pro-inflammatory protein, increase in DKD patients and mice models correlating well with disease progression. Podocytes might be the primary renal cells that respond to the increased SAA by inducing nuclear factor-kappa B (NFκB) signaling[35].
Inflammation-mediated endothelial injury is multifaceted. NET inhibition by GSK484, a selective and reversible peptidyl arginine deiminase 4 (PAD4, a marker of NETs) inhibitor, ameliorates endothelial dysfunction in murine and human endothelial cells exposed to hyperglycemia[30]. Insulin-like growth factor-binding protein 5 (IGFBP5) is upregulated in DKD and enhances inflammation by metabolically reprogramming glomerular endothelial cells. Pro-inflammatory factors, like interleukin 6 (IL6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP1), and intercellular adhesion molecule 1 (ICAM1), are induced by IGFBP5, which itself is upregulated by hyperglycemia in endothelial cells. This inflammatory action of IGFBP5 is dependent on its regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a glycolytic enzyme[36]. Suppressing PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response in cardiac endothelial cells. While this work focused on cardiac fibrosis, similar signaling might play a role in DKD renal fibrosis[37]. Allograft inflammatory factor-1 (AIF-1) is upregulated in glomerular endothelial cells in the diabetic kidney, and knocking it down ameliorates kidney inflammation and injury. AIF-1 enables glomerular endothelial cell inflammation and OS in DKD via NFκB signaling[38]. Panzer et al. showed the differential regulation of monocyte/macrophage recruitment in the glomerulus vs tubules: MCP1 was more important in the glomeruli and osteopontin in the tubular compartment[39].
The most characteristic of all diabetic glomerular changes is GBM thickening[32,40]. It starts well before DKD diagnosis, within a few years of diagnosis of diabetes. However, the thickening is more pronounced in DKD. Changes in the composition, charge, or architecture of the GBM associated with thickening could contribute to the pathogenesis of DKD. Stiffening of the GBM resulting from the thickening may also facilitate glomerular injury through hemodynamic mechanisms[31].
The mesangium undergoes numerous progressive changes with DKD: mesangial cell proliferation and hypertrophy, mesangial matrix expansion, and mesangiolysis[32,40]. USP25, a deubiquitinating enzyme, is upregulated in the mesangial cells and infiltrating macrophages in a diabetic kidney. It ameliorates DKD by inhibiting TRAF6-mediated inflammatory responses[41]. The expansion of the mesangium reduces the capillary surface area, contributing to glomerular hypertension and reduced glomerular filtration[32]. Thus, glomerular inflammation causes increased permeability of the filtration barrier. This allows proteins, like albumin, to leak into the urine, causing microalbuminuria and, subsequently, proteinuria, which is used for diagnosis and prognosis.
Vascular inflammation
Kidneys represent one of the most vascular organs in the body and, despite their relatively smaller size and weight, receive 25% of the cardiac output. Most serious long-term complications of diabetes, including DKD, are mediated by vascular involvement. Oxidative stress and inflammation affecting the renal vasculature play a crucial role in the development and progression of DKD [Figure 2]. Arteriolosclerosis and arteriolar hyalinosis that develop as a result of these intrarenal processes are essential structural changes that ultimately contribute to the progression of DKD. Vascular inflammation is a precursor to arteriolosclerosis. Recent studies underscore the significance of NLRP3 inflammasome activation, which may contribute to vascular inflammation in diabetes[42].
Figure 2. Vascular inflammation in DKD. The schematic illustrates the signaling pathways and mechanisms leading to vascular inflammation in DKD. Both hemodynamic and metabolic alterations in diabetes contribute to the activation of these pathways. While the nitric oxide pathway may be upregulated in the early phases of DKD and contribute to hyperfiltration, NO levels decrease as the course progresses, partly due to NO quenching by superoxide, leading to peroxynitrite, which stimulates inflammatory cytokines. Similarly, endothelin activation by hemodynamic and metabolic factors leads to endothelial injury and vascular inflammation. Chronic uncontrolled hyperglycemia leads to advanced glycation endproducts, which trigger inflammasome and oxidative stress. Ultimately, all the signaling alterations lead to vascular inflammation, contributing in a major way to renal demise in diabetes. AGEs: Advanced glycation endproducts; RAGE: receptor for AGE; TNF-α: tumor necrosis factor-alpha; IL: interleukin; NLRP3: NOD-like receptor family pyrin domain-containing 3; ROS: reactive oxygen species; NO: nitric oxide.
In diabetes, all cells are chronically exposed to high plasma glucose levels; however, some get affected more than others and manifest progressive dysfunction. Endothelial cells cannot lower their glucose transport in response to high glucose levels[43]. This results in much higher levels of intracellular glucose, which trigger the generation of inflammatory inducers and mediators that contribute to the development of diabetic complications, including DKD. Markers of inflammation like C-reactive protein (CRP), vascular cell adhesion molecule (VCAM), and IL1 correlate with microvascular complications in diabetic patients[44]. However, high glucose exposure can only cause inflammation in human vascular cells if primed with an inflammatory stimulus such as IL1β or TNF-α[45,46]. The excess intracellular glucose is diverted to the pentose phosphate pathway, providing additional substrate for NOX and increasing free radicals[47]. The pro-oxidant environment further exacerbates inflammation and tissue damage.
Hyperglycemia-induced endothelial dysfunction increases vascular susceptibility to shear, oxidative, and other stressors[47]. With subsequent microvascular rarefaction, it reduces blood flow, causing hypoxia. Renal hypoxia induces compensatory changes in blood flow, metabolism, and glomerular neoangiogenesis[32,48,49]. Decreased blood flow, impaired oxygen utilization by mitochondrial dysfunction, and microvascular thinning contribute to hypoxia and ischemia in the proximal tubular compartment[50-52]. AGEs also contribute to vascular complications of diabetes, mediated by methylglyoxal derivatives, which are metabolized by glyoxalase-1. Inducers of glyoxalase-1, such as t-resveratrol-hesperetin, have proven beneficial for DKD in preliminary trials by reducing insulin resistance and vascular inflammation[53]. NETs are usually formed in the vasculature near endothelial cells[30]. They can cause endothelial cell death and vascular necrosis[54,55].
Recent clinical observations revealed that a significant proportion of patients with DKD (~30%-40%) do not exhibit significant proteinuria. In these non-proteinuric DKD patients, vascular disease, particularly arteriosclerosis, is widely prevalent and often caused by inflammation. Vasoactive factors such as endothelin, nitric oxide, and angiotensin, along with inflammatory mediators such as NF-kB, peroxynitrite, and TNF-α, play a major role in vascular inflammation that leads to sclerosis.
Tubulointerstitial inflammation
Inflammation is one of the primary triggers of tubulointerstitial injury during DKD, leading to fibrosis and functional loss. Tubulointerstitial lesions can precede or occur irrespective of glomerular lesions, as evidenced by normo-proteinuric or non-proteinuric DKD[56]. Impaired albumin uptake by proximal tubule cells might contribute to microalbuminuria, irrespective of glomerular damage[57]. Sustained hyperglycemia causes hypertrophy and proliferation in tubular epithelial cells, increasing reabsorption of glucose and sodium - the damage-causing stimuli. An aberrant tubuloglomerular feedback results in increased intraglomerular pressure and hyperfiltration. Thus, a more tubule-centric view of DKD is warranted[50,58].
High glucose exposure triggers MAPK and protein kinase C (PKC) signaling in renal tubular cells, stimulating the expression of pro-inflammatory molecules, such as IL6, MCP1, and osteopontin[39,59]. AGEs also trigger tubulointerstitial inflammation. Proximal tubules are the primary sites for AGE resorption and are induced in their presence to produce pro-inflammatory molecules (IL8, ICAM1)[50,60,61]. These cytokines and chemokines enable the recruitment and infiltration of immune cells like monocytes and macrophages in the renal tubulointerstitium, which further increases pro-inflammatory, profibrotic, and antiangiogenic factors, culminating in interstitial fibrosis and tubular atrophy (IFTA). The interstitial macrophage aggregation has prognostic value in DKD as it correlates well with the progression of the disease[62,63]. The expression of myostatin, a member of the transforming growth factor-beta (TGF-β) superfamily, increases in DKD predominantly in the tubulointerstitium. It induces pro-inflammatory and profibrotic signaling (NFκB, CCL2, SMAD) in proximal tubules, suggesting its role in interstitial fibrosis in DKD[64].
Tubular epithelial cells typically prefer fatty acid oxidation (FAO) as an energy source; however, in DKD, FAO gets dysregulated, resulting in an increased dependence on glycolysis for energy and intracellular lipid deposition, which increases apoptosis and dedifferentiation[65,66]. High glucose and AGEs enhance cellular lipid synthesis and free fatty acid and cholesterol uptake, contributing to intracellular lipid accumulation, which fosters inflammation, OS, and endoplasmic reticulum stress[50,67,68]. Kidneys of type-2 DKD patients and murine models also show ectopic lipid deposits predominantly in the proximal tubular compartment. Sustained hyperglycemia increases the expression of adipose differentiation-related protein (ADRP) and sterol regulatory element binding protein 1 (SREBP1) in proximal tubule cells, along with other markers of tubulointerstitial damage. In vitro experiments indicate that they mediate tubular inflammation[69]. Perirenal fat accumulation is pathogenetic in DKD. Adipocytes secrete adipokines and cytokines, promoting inflammation and OS and mediating kidney function decline[70,71].
Since tubulointerstitial lesions could be the first pathology associated with DKD, biomarkers of tubular function might have diagnostic and prognostic value, e.g., serum levels of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), or urine levels of retinol-binding protein 4, cystatin C, and fatty acid binding protein 1[50,58].
Oxidative stress
OS and chronic inflammation are intertwined in DKD, each worsening the other in a slow feed-forward loop[72-74]. In one of the first reports suggesting a causal role of hyperglycemia in immune activation, Esposito et al. showed that acute hyperglycemia spikes circulating pro-inflammatory cytokine concentrations (IL6, IL18, and TNF-α) through an oxidative mechanism[75]. Reactive oxygen species (ROS) produced during inflammation directly damage renal cells and induce inflammatory signaling to recruit immune cells for repair, which causes more OS, thus completing the loop. Eventually, this progresses to fibrosis and endothelial dysfunction[75-77].
An imbalance between the producers and quenchers of ROS results in their accumulation. Numerous pathways contribute to ROS generation in diabetic kidneys, e.g., the uncoupling of nitric oxide synthases (NOS), NOX, advanced glycation, and mitochondrial dysfunction[73,78-80]. Hyperglycemia triggers mitochondrial dysfunction and superoxide release in glomerular endothelial cells, which secrete factors to initiate podocyte apoptosis[81].
Programmed cell death (PCD) mechanisms of apoptosis, autophagy, and necroptosis play important roles in DKD, especially in damaged podocytes and proximal tubule cells[82]. Recently, the focus has increased on ferroptosis, an iron-dependent form of PCD, in the pathogenesis of DKD[83]. ROS-induced autophagy promotes intracellular iron accumulation and ferroptosis[84]. Hyperglycemia and inflammation trigger ferroptosis in renal endothelial and tubular cells, reducing their viability and contributing to endothelial and tubular dysfunction in DKD[85,86]. Iron accumulation, lipid peroxidation, and decreased antioxidant activity - processes that drive ferroptosis - increase in renal tubular cells cultured in high glucose, and upregulating the protective antioxidant signaling reduces diabetes-related ferroptosis, delaying DKD progression[86,87].
Pathogenesis of DKD is inseparable from ROS overactivation. While a significant contributor to DKD, antioxidants have not fared well in clinical trials for DKD, but whether they amplify the effect of other therapies remains to be seen.
Immune cell infiltration
Bioinformatic studies are revealing the changes in the landscape of immune cells in the DKD kidney. More memory B cells, T cells, activated natural killer (NK) cells, macrophages, resting dendritic cells, and resting mast cells were found in the glomerulus of patients with DKD, with fewer naïve B cells, resting NK cells, activated mast cells, and neutrophils[88]. With pooled samples of glomerular and tubular DKD data sets, Wang et al. verified more macrophages and fewer Treg and Th2 cells in diabetic kidneys. Immune cells were identified primarily in the interstitium compared with the glomeruli[89]. Pathway analyses show activation of leukocyte trans-endothelial migration, T-cell receptor signaling, NOD-like receptor signaling, chemokine signaling, cell adhesion molecules, extracellular matrix (ECM) receptor interaction, and phagocytosis[88,89]. Using single-cell RNA sequencing followed by verification in human patient biopsies,
Fibrosis and scarring
Prolonged inflammation triggers kidney fibrosis - a hallmark manifestation in progressive CKD, irrespective of the primary insult. Deregulated wound healing leads to excessive production and accumulation of ECM proteins, such as fibronectin and collagens[90]. When kidneys are injured, local fibroblasts and pericytes are activated, increasing their contractility, secreting inflammatory mediators, and synthesizing ECM components, which trigger wound healing. However, when the damage is repetitive (e.g., DKD), the ECM proteins accumulate in the parenchyma, resulting in tissue disruption, renal dysfunction, and organ failure[91,92].
Fibrosis in the DKD kidney is indicated by the presence of tubule atrophy, chronic interstitial inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Renal function and prognosis correlate better with tubulointerstitial fibrosis than early glomerular changes[93]. A complex interaction ensues between the injured renal parenchyma (tubular cells) and multiple non-parenchymal cells (immune and mesenchymal cells) within the scarring areas. Wang et al. implicated the role of sonic hedgehog (Shh) secreted from senescent tubular cells along with other senescence-associated proteins in fibroblast activation and proliferation in DKD[94]. Several sources contribute to the accumulation of activated myofibroblasts in different proportions: transformation of the resident fibroblasts and mesenchymal stem cells, recruitment of fibroblasts from the bone marrow, epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells[91,92].
PATHWAYS
NFκB pathway
NFκB regulates the expression of the primary mediators of inflammation. Sensing PAMPs or DAMPs, PRRs activate a signaling cascade that culminates in freeing NFκB from its inhibitor IκB (inhibitor of NFκB) to translocate to the nucleus and activate target gene expression [Figure 3]. IκB is a target of NFκB; this allows for quick and transient activation of this pathway[95,96].
Figure 3. Inflammatory signaling pathways in DKD. The schematic summarizes the inflammatory signaling pathways that drive DKD. From left to right: NFκB pathway, JAK/STAT pathway, MAPK pathway, complement cascade, inflammasome signaling. NFκB remains inhibited and retained in the cytosol under physiological conditions. Activated pattern recognition receptors activate the IKK complex, which phosphorylates IκB, causing its degradation and freeing NFκB to translocate to the nucleus and activate target gene expression. Cytokine receptors dimerize upon detecting their cytokines, leading to transactivation of the associated JAKs. Activated JAK recruits and phosphorylates the transcription factor STAT, which then dimerizes and activates its target gene expression. MAPK pathway is a phosphorylation cascade resulting in activated MAPK translocating into the nucleus and transcribing target genes. When triggered, the complement system results in a cascade of proteolytic enzymes culminating in the formation of membrane attack complex and pro-inflammatory mediators. NFκB mediates the assembly of inflammasomes, which in turn release pro-inflammatory inducers and mediators. AGEs: Advanced glycation endproducts; DAMP: damage-associated molecular patterns; GSDMD: gasdermin D; IKK: IκB kinase; IL: interleukin; IκB: inhibitor of NFκB; JAK: Janus kinase; MAP2K: mitogen-activated protein kinase kinase; MAP3K: mitogen-activated protein kinase kinase kinase; MAPK: mitogen-activated protein kinase; MASP: MBL-associated serine protease; MBL: mannose-binding lectin; NFκB: nuclear factor kappa B; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; TF: transcriptional factor; Ub: ubiquitin.
All resident kidney cells possess the capability of activating NFκB. It is rapidly activated by diverse stimuli, including hyperglycemia, AGEs, mechanical stress, ROS, inflammatory cytokines, and angiotensin II - all present in excess in the diabetic milieu. Activated NFκB stimulates the transcription of pro-inflammatory cytokines, chemokines, and adhesion molecules[95,97]. The activation of NFκB and its targets correlates with the degree of tubular damage and can indicate renal damage progression in DKD patients[98]. Tubular injury in patients with DKD correlates with TLR4 upregulation. TLR4/NFκB signaling induces gasdermin
JAK/STAT signaling
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a key signaling node in DKD progression [Figure 3]. Inhibitory regulators of this pathway include the constitutive protein inhibitors of activated STAT (PIAS) and protein tyrosine phosphatases (e.g., PTP1B) and the inducible suppressors of cytokine signaling (SOCS). The constitutive presence of inhibitors allows for a transient activation of this pathway. The JAK/STAT pathway is activated by a range of metabolism-related cytokines and hormones, such as IL3, IL6, and angiotensin II[101-103].
JAK/STAT signaling is implicated in multiple aspects of DKD: inflammation, fibrosis, RAAS, autophagy, and EMT[101,103-107]. Higher levels of JAK2 are seen in the glomerular and tubulointerstitial compartments of DKD-patient kidneys. Upregulation of JAK1-3, STAT1, and STAT3 were seen in DKD patients with eGFR significantly correlating with tubulointerstitial JAK1-3 and STAT1 expression[108]. Genetic mutants of STAT3 in mice show that IL6-mediated activation of STAT3 is required for diabetic glomerulopathy development. STAT3 knockdown reduced STAT3 phosphorylation and inflammatory marker expression, including IL6, MCP1, activated NFκB, type IV collagen, TGF-β, and ICAM1[101]. Chen et al. found that hyperglycemia activated JAK/STAT signaling, inhibited autophagy, increased podocyte apoptosis, and aggravated renal injury. Inhibiting the pathway by ruxolitinib, a JAK inhibitor, reversed the decrease in autophagy[106]. A protective role of Forkhead box 1 (FOXO1) on proximal tubule injury in DKD is mediated via JAK/STAT inhibition. FOXO1 downregulation increased the expression of pSTAT1, activated EMT, and initiated the intrinsic apoptotic pathway. Increasing FOXO1-mediated STAT1 inhibition alleviated tubulointerstitial fibrosis, tubular EMT, and apoptosis[109]. SOCS3 overexpression can reduce AGE-induced EMT by inhibiting the JAK2/STAT3 signaling in proximal tubule cells[107].
Members of this pathway are being considered for their therapeutic potential in DKD. Treatment with baricitinib (JAK1/JAK2 inhibitor) improved proteinuria and levels of biomarkers of inflammation in urine and blood (urine C-X-C motif chemokine 10 and urine C-C motif ligand 2, plasma soluble TNF receptors 1 and 2, ICAM1, and SAA) of subjects with DKD[110]. El-Kady et al. showed that ruxolitinib improved proteinuria, renal inflammation, and fibrosis in a rat model of T1DM[111].
MAPK pathway
MAPKs, a family of serine/threonine kinases, function through three pathways: the extracellular signal-regulated kinase (ERK)-MAPK, p38-MAPK, and Jun N-terminal kinase (JNK)-MAPK pathways. Initiated by an external stimulus, such as high glucose, MAPKKK phosphorylates MAPKK, which phosphorylates and activates MAPK to translocate into the nucleus and transcribe target genes[112] [Figure 3]. MAPK targeting shows promise, with several studies claiming that pathway inhibition alleviates DKD. For example, MAPK inhibition can reverse KIM-1-mediated macrophage M1 transformation and migration[113]. Antioxidant treatment reduces MCP1 and phosphorylated JNK levels in mesangial cells, reducing inflammation[114]. Blocking JNK signaling inhibits interstitial myofibroblast accumulation. JNK1/2 deletion does not inhibit renal fibrosis; however, JNK1 deletion decreases renal tubular apoptosis[115]. Inhibiting the ERK pathway reduces nitrite levels in stimulated macrophages by decreasing TNF-α production. ERK stimulates, and p38 inhibits, inducible NOS (iNOS, an inflammatory mediator)[116]. ERK and p38 also correlate with glomerular and tubulointerstitial lesions in patients with DKD[117].
p38 is activated in hyperglycemic conditions within podocytes, mesangial cells, and tubular cells, coinciding with TGF-β[118,119]. p38 expression is elevated in early diabetes with increased MAPKK3/6 and cAMP-responsive element binding protein (CREB) and is associated with renal hypertrophy and fibrosis[120]. p38-dependent CREB activation can mediate angiotensin II and lipoxygenase-induced fibronectin expression and cellular growth in mesangial cells[121]. p38 inhibition diminishes albuminuria in T1DM mice. p38 might regulate nephrin endocytosis in podocytes, as its inhibition leads to a loss of nephrin. p38 is phosphorylated at Ser1146 in diabetic mice, which then interacts with nephrin, leading to its endocytosis[119].
Complement cascade
The complement system is an innate immune defense mechanism and immune-metabolic regulator. It is a cascade of plasma proteins activating the next protein by proteolytic cleavage to induce inflammatory responses. Complement activation occurs by classical, alternative, and lectin pathways, with the latter triggered by the binding of lectins, such as mannose-binding lectin (MBL), to aberrant carbohydrates expressed on the surface of damaged cells. All three pathways converge at complement 3 (C3), which initiates an enzymatic cascade to generate the effector molecules, including C3a, C5a, and C3b, and ultimately, the membrane attack complex (MAC), forming pores in the target cell membranes, thereby killing them. C3a and C5a are potent pro-inflammatory mediators[122,123] [Figure 3].
The complement system is activated in DKD[10,123-126]. Hyperglycemia results in glycated proteins, which can directly activate the complement system by binding MBL and initiating pro-inflammatory signaling. Circulating MBL level is a robust biomarker for the development and progression of DKD[125,127]. Growing evidence suggests that MBL, C3, and MAC contribute to renal injury in the hyperglycemic milieu[123,128,129]. Antagonists of C5a and C3a receptors improve kidney fibrosis in diabetic rats[124].
NLRP3 inflammasome
Large protein complexes (> 700 kDa) containing caspase-1, apoptosis-associated speck-like protein (ASC), and NLRP3 form within stimulated immune cells such as monocytes, macrophages, and dendritic cells. These are called inflammasomes. On detecting danger signals, such as microbial motifs or DAMPs, NLRP3 assembles the NLRP3 inflammasome, causing caspase-1-dependent pro-inflammatory cytokine release and pyroptosis[130,131] [Figure 3]. The hyperglycemic milieu of DKD contains a surplus of stressors required for the assembly and activation of NLRP3 inflammasome. Inflammatory inducers activate NFκB signaling, expressing and activating NLRP3, pro-IL1β, and pro-IL18, and transcriptional protein modifications such as ASC phosphorylation and NLRP3 deubiquitination. A secondary stimulus, like ROS, activates the inflammasome by oligomerizing inactive NLRP3 and activating pro-caspase-1[130].
Podocyte-specific NLRP3 inflammasome activation is necessary and sufficient for the expression of DKD in hyperglycemic mice. Podocyte-specific NLRP3 gain-of-function mutant aggravated hyperglycemia-induced kidney damage (albuminuria, mesangial expansion, and GBM thickening), whereas loss of NLRP3 or caspase-1 was renoprotective[33]. NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under hyperglycemic stress[30]. Inhibiting NLRP3 prevents hyperglycemia-induced lipid accumulation in podocytes and, therefore, podocyte damage[132]. Thus, NLRP3 inflammasomes exacerbate inflammation by promoting the release of pro-inflammatory cytokines, and sustained activation contributes to renal inflammation, fibrosis, and kidney damage.
Wnt/β-catenin
Essential for embryonic development, the Wnt/β-catenin pathway plays a role in DKD and impacts inflammatory pathways, such as NFκB and JNK[133-145] [Figure 4]. Snail, a Wnt target, is a marker of EMT and is associated with inflammation. During EMT, TNF-α triggers Snail and inhibits its ubiquitination[136,145]. Snail knockout in tubular cells displays lower macrophage infiltration and NFκB signaling, indicating that Wnt signaling mediates tubular inflammation[145]. IKKα plays a role in β-catenin target gene expression. TGF-β-mediated Wnt/β-catenin activation leads to increased binding between IKKα and β-catenin[143]. JNK binds to the E-cadherin/β-catenin complex as DKD progresses, showing JNK to be a player in EMT during DKD. JNK phosphorylates β-catenin and remodels the actin cytoskeleton[144].
Figure 4. Wnt and TGF-β signaling pathways. To the left of the figure, Wnt canonical and non-canonical pathways are demonstrated. The top left of the sphere features the canonical Wnt/β-Catenin pathway with no ligand bound, leading to the formation of the
Multiple RAAS players are direct targets of Wnt/β-catenin signaling. Inhibiting β-catenin in a mouse model of CKD led to a significant reduction in proteinuria, suggesting an interaction between RAAS and Wnt/β-catenin signaling in inflammation[140-142].
The Wnt/β-catenin pathway also impacts macrophage accumulation in the kidneys. In human, animal, and cell models, Wnt5a binds CD146, inducing non-canonical signaling-mediated TNF-α, IL6, and CCL2[138]. Stimulated human peripheral blood mononuclear cells (PBMCs), Wnt5a triggers non-canonical signaling-mediated macrophage activation. Silencing Wnt5a decreases inflammation[139]. A co-culture of chemokine-producing myeloid cells and early myofibroblasts exhibited β-catenin nuclear translocation during EMT. Blocking Wnt reduced β-catenin nuclear translocation, preventing EMT[146].
TGF-β/SMAD
TGF-β, a profibrotic factor, drives EMT within the kidney via SMAD proteins[147] [Figure 4]. Inhibiting the pathway suppresses renal fibrosis via expressing micro-RNA-29 (miR-29) and repressing miR-192 and
Urinary levels of TGF-β can be a marker for IgA nephritis and glomerulosclerosis, as patients with these disorders have higher levels of urinary TGF-β and lower TGF-β receptors[150,151]. TGF-β is also correlated with the progression of interstitial fibrosis[150]. In rats with ischemia-reperfusion injury, inhibiting the TGF-β pathway via pirfenidone demonstrates renoprotective effects by relieving inflammation and fibrosis[152]. While inhibiting all three TGF-β isoforms alleviates renal fibrosis in rats, no clinical trials targeting TGF-β have succeeded[152,153].
Hyperglycemia-driven macrophage inflammatory protein-3a (MIP-3a) induction in renal proximal tubules is TGF-β1-dependent[154]. TGF-β is important for mitochondrial quality control in the proximal tubules. In mice, deleting TGF-β receptor 2 (TbR2) impairs mitochondrial complex 1, reducing quality control and increasing inflammation, promoting oxidative stress[151]. TGF-β null mice develop autoimmune disorders, while TbR2 deficiency induces a lethal inflammatory disorder 8-10 weeks following induction. When bone marrow from TbR2 deficient mice is transferred to healthy mice, the mice encounter inflammation and death[155]. Contrastingly, in mouse matrix-producing interstitial cells (MPICs), deletion of TbR2 did not significantly impact renal fibrosis during unilateral ureteral obstruction (UUO) and aristolochic acid-induced nephropathy. Collagen production was diminished, suggesting that there are complex mechanisms involved in TbR2 regulation[156]. TGF-β is pertinent for inflammation and can initiate Wnt target gene transcription and activate p38 and ERK[145].
PLAYERS
Numerous factors in the diabetic milieu induce inflammation: hyperglycemia[25,47,59,154,157], hyperlipidemia[158-160], reactive oxygen species[74,77,78,121], AGEs[68,107,161], and hypertension[162-164], to name a few. Chronic low-grade inflammation damages tissue, resulting in the production of DAMPs, which exacerbate inflammation.
Damage-associated molecular patterns
DAMPs are endogenous non-microbial inflammation inducers. Released from damaged cells, these danger molecules bind PRRs, activating inflammatory cascades to start the repair process. As expected, DAMPs can be pathogenic in inflammatory diseases[165,166]. DAMPs originate from different compartments: the extracellular matrix, such as fibronectin and tenascin C; different intracellular compartments, such as nuclear high-mobility group box 1 (HMGB1) and histones, cytosolic uric acid and heat shock proteins (HSPs), and mitochondrial DNA and ROS; and plasma proteins, like fibrinogen and SAA[166].
Detectable in the urine of patients with glomerular disease, soluble fibronectin induces chemokine expression in tubular cells by activating Src tyrosine kinases, ERK1/2, and NFκB[167]. Tenascin C promotes the proliferation of kidney interstitial cells via STAT3 activation[168]. When released to the extracellular space, HMGB1 (a redox-sensitive DNA chaperone) induces inflammation by binding to TLR2, TLR4, and RAGE[169]. Hyperuricemia is a common finding in DKD. Uric acid activates the immune system and affects resident kidney cells toward a pro-inflammatory and profibrotic state[170,171]. SAA, a clinical marker for active inflammation, binds to and activates multiple PRRs (TLR2, TLR4), increasing NFκB activity and inflammatory mediators[35,166]. Several DAMPs are compelling candidates as biomarkers and therapeutic targets for DKD.
Pattern recognition receptors
Present primarily on the surface of immune cells, PRRs detect microbes or tissue damage by binding to specific molecular structures (PAMPs or DAMPs) and induce signaling cascades to produce inflammatory mediators. With chronic inflammation driving DKD, it is natural that PRRs play an essential role, and mounting evidence verifies this.
TLR2 and -4 are expressed on the surface of renal tubular epithelial cells, endothelial cells, podocytes, and mesangial cells and are implicated in mediating inflammation in these compartments in DKD[172-174]. Enhanced TLR4 expression and signaling were reported in renal glomeruli and tubules of patients with type 2 DKD and microalbuminuria. A 6-year follow-up of patients with microalbuminuria showed an association between enhanced glomerular TLR4 expression and renal functional decline[175]. TLR2 is likely the predominant long-term mediator of NFκB-dependent inflammation in proximal tubules[173]. The absence of TLR2 attenuates the pro-inflammatory state in a type 1 DKD mouse model[176].
NLRs, the other major PRRs, are present in the cytosol and sense intracellular PAMPs and DAMPs. NLRP3 is the most researched NLR in diabetes and DKD. NLRP3 oligomerizes to form inflammasome complexes with the adaptor protein ASC and the effector protein pro-caspase 1 (see Section "NLRP3 inflammasome"). Several triggers activate NLRP3, including fatty acids, uric acid, extracellular ATP, hyperglycemia, SAA, and mitochondrial ROS[157]. NLRP3 inflammasome exacerbates inflammation in glomerular endothelial cells and podocytes, as reviewed before[30,33]. Kim et al. describe an inflammasome-independent role of NLRP3 in renal tubular cells in mitochondrial ROS production in acute hypoxic renal injury[177]. The contribution of such mechanisms in CKDs remains to be seen.
AGEs are non-enzymatically glycated proteins, lipids, and nucleic acids, and their accumulation increases in diabetes[60]. AGE accumulation in the kidneys upregulates the expression of its receptor (RAGE)[178]. AGE-RAGE induces inflammation and oxidative stress and promotes fibrosis in the diabetic kidneys via canonical pro-inflammatory and profibrotic signaling, like NFκB, MAPK, and TGF-β/SMAD, contributing to DKD pathogenesis. Targeting AGEs/RAGE by pharmacotherapy, anti-glycating agents, or diet improves DKD[60,179].
MBL, a PRR, activates the lectin pathway of the complement system upon recognizing PAMPs or altered self-antigens. High MBL increases the risk of proteinuria and all-cause mortality in T1DM and T2DM[125,180,181]. A large-scale study reported a U-shaped association of serum MBL levels with cardiovascular events and all-cause mortality in T2DM, suggesting that low and high serum MBL expression are risk factors[182]. This makes sense when one sees inflammation playing a protective role and deregulated inflammation as damaging. MBL might, therefore, have predictive and prognostic value in DKD, but more studies are required[127,183].
Pro-inflammatory mediators
Cytokines are small secreted polypeptides that stimulate the movement of immune effector cells toward the sites of inflammation, infection, or trauma. Cellular communication mediated by cytokines can be autocrine or juxtacrine for signal amplification or paracrine to recruit blood-borne immune effector cells. Produced in response to infection or trauma via inflammatory signaling, cytokines recruit, stimulate, and proliferate immune cells. Examples include ILs, chemokines, interferons, and TNFs. They are subdivided based on the nature of their function in the immune response. Pro-inflammatory cytokines perpetuate inflammation and are necessary in the initial stages of an inflammatory response, while anti-inflammatory cytokines control pro-inflammatory cytokines. Cytokines have long been implicated in the progression of DKD with prognostic and therapeutic implications[184].
Pro-inflammatory cytokines
Numerous cell types in the kidney can synthesize inflammatory cytokines, including the resident renal cells (glomerular, endothelial, tubular, and mesangial cells) and blood-borne cells. The production of these cytokines increases as nephropathy progresses, with an independent relationship found between these inflammatory molecules and kidney function[21,95,185-188].
Elevated levels of IL6 and CRP, representing an ongoing metabolic storm, are risk factors for T2DM in apparently healthy adults[8,9]. Patients with T2DM have higher levels of circulating pro-inflammatory cytokines (IL6, TNF-α), indicating a continued inflammatory state[7,72,189,190]. Moreover, hyperglycemia acutely increases circulating pro-inflammatory cytokine concentrations, and this effect is more pronounced in subjects with impaired glucose tolerance, thus confirming a direct causal effect of hyperglycemia in activating the immune system in diabetes[75]. Urinary and serum levels of pro-inflammatory cytokines IL1α, IL8, and IL18 correlate with biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of proximal tubular dysfunction (KIM-1, NAG) in the early stage of DKD in T2DM[191]. IL1β, a macrophage-derived pro-inflammatory cytokine, stimulates the proliferation of renal fibroblasts and increases fibronectin and collagen production in a TGF-β-dependent mechanism, suggesting its role in renal fibrosis[192]. TNF-α contributes to the pathogenesis of DKD by regulating immune cells and cytokine release, as well as directly inducing ROS production[18,193]. Thus, pro-inflammatory cytokines perpetuate inflammation, further damaging the kidney tissue and contributing to kidney injury and fibrosis.
Chemokines
Chemokines and their receptors promote inflammatory cell interactions and recruitment to the injury site. High glucose and inflammatory cytokines increase the expression of MCP1 [also known as CC motif chemokine 2 (CCL2)] in mesangial and tubular cells[98,194]. Serum MCP1 levels correlate with albuminuria and are an independent risk factor for developing type 2 DKD[195]. Urinary levels of MCP1 correlate with UAE and eGFR[196]. Both serum and urinary levels of MCP1 can be diagnostic and prognostic biomarkers of DKD. Another potent chemoattractant for monocytes, macrophages, granulocytes, and T cells, CCL5 (also known as RANTES), correlates with proteinuria. It is produced in various renal cells, including fibroblasts, mesangial, and tubular cells, when induced by RAAS activation, pro-inflammatory cytokines, and protein overload[18,95,98]. A type 1 DKD animal model shows increased expression of fractalkine (CX3CL1) and its receptor[197]. Together, they mediate ECM production in mesangial cells and hypertension-induced interstitial fibrosis[198,199].
Adhesion molecules
Cell adhesion molecules aid the migration and homing of immune effector cells, like macrophages, to the kidney. Overexpression of cell adhesion molecules, such as ICAM1 and VCAM1, on the surface of endothelial and tubular cells aids in their capture of circulating macrophage precursors and leucocytes[36,200,201]. Glomerular hyperfiltration rather than hyperglycemia triggers the increase in ICAM1 expression in the early stages of DKD. Mononuclear cell infiltration into diabetic glomeruli is prevented by anti-ICAM1 antibody[201]. AGEs induce upregulation of ICAM1 expression in tubular and mesangial cells[61,202]. VCAM1 is another adhesion molecule implicated in immune cell infiltration in DKD. VCAM1 expression increases in endothelial, tubular, and infiltrating cells in the renal interstitium in a diabetic state[200,203]. Circulating VCAM1 levels increase and correlate with UAE in patients with T2DM[204].
Anti-inflammatory mediators
An inflammatory response is supposed to aid the organism in healing from a pathological insult or injury, but its dysregulation causes it to become an insult. The balance between pro- and anti-inflammatory mediators dictates the overall effect of inflammatory response.
Anti-inflammatory cytokines
Pro-inflammatory cytokines initiate the early responses and amplify inflammatory reactions, whereas anti-inflammatory cytokines, including IL4, IL10, IL11, and IL13, have the opposite effect in that they limit the pro-inflammatory cytokine response[205]. A mouse model of albumin overload-induced tubulointerstitial injury showed that IL4 receptor alpha (IL4Rα) is upregulated in the proximal tubule cells via JAK3/STAT6 signaling. Suppressing IL4 signaling in these cells reverses the inhibitory effect of higher albumin concentration without changing albumin endocytosis[206]. Whether IL4 signaling may play a protective role in DKD remains to be seen.
A recent systematic review found an inverse relationship between IL10 levels and oral disease in patients with diabetes[207]. IL10 deficiency accelerates diabetes by promoting neutrophil generation and activating CD4+ T-cells in a mouse model of T1DM[208]. The anti-inflammatory action of IL10 is lower in whole blood cultures prepared from patients with T2DM, although the serum levels of IL10 are not significantly different, suggesting an IL10-hyporesponsive state in diabetes[209]. IL10 knockout intensified kidney inflammation and fibrosis[210]. Some polymorphisms of the IL10 promoter have a protective effect on the risk of DKD in T2DM[211]. IL10 also exhibits multiple renoprotective effects after diabetic myocardial infarction: it reduces acute renal inflammation, upregulates heme clearance, attenuates fibrosis, and reduces proteinuria. IL10 reduces the production of ROS in proximal tubule cells and collagen synthesis in fibroblasts[212].
Identified based on its similarities to IL6, IL11 possesses anti-inflammatory activity. It is a proposed therapeutic agent for treating chronic inflammatory diseases such as Crohn's disease and rheumatoid arthritis. However, in the kidneys, the effect of this cytokine is unusual. IL11 is upregulated by TGF-β and required for its profibrotic effects. Produced initially by tubular cells of a damaged kidney, it stimulates EMT in an autocrine manner. Neutralizing IL11 significantly reduces the extent of fibrosis, inflammation, and tubular damage. Anti-IL11 promotes kidney regeneration and reverses EMT and renal dysfunction[213,214]. These studies suggest IL11 signaling as a therapeutic target for DKD; however, one must also recognize how this signaling affects other tissues. For example, IL11 levels detected in gingival crevicular fluid decrease progressively with decreasing glycemic control and increasing periodontal disease in patients with T2DM[215].
IL13 regulates gluconeogenesis in hepatocytes via STAT3; mice lacking IL13 develop hyperglycemia and insulin resistance, implicating IL13 in the development of diabetes[216]. Several studies show that serum levels of anti-inflammatory cytokines increase significantly in DKD patients and are positively correlated with DKD severity and risk of cardiovascular events but may not correlate with markers of inflammation[217-219]. Several explanations might explain such confusing results. Cytokines, like IL6 and IL4, can have pro- or anti-inflammatory effects depending on the context. Anti-inflammatory cytokines might be unable to balance the overwhelmingly pro-inflammatory state. Our lack of a better understanding of these cytokines in the context of DKD warrants deeper, well-designed studies.
Suppressors of cytokine signaling
SOCS is a family of eight intracellular, cytokine-inducible proteins that can inhibit JAK/STAT signaling. Diabetic conditions induce SOCS in podocytes, mesangial, tubular, and inflammatory cells. SOCS inhibits high-glucose-induced JAK/STAT signaling in mesangial and tubular cells and normalizes creatinine clearance, UAE, and weight loss in diabetic rats mediated by diminishing inflammation[220].
Pro-resolving mediators
An unresolved acute inflammation converts to pathogenetic chronic inflammation. A distinct coordinated program to resolve inflammation commences soon after an inflammatory response begins. Broadly, pro-resolving mechanisms include an increase in phagocytosis, efferocytosis, and cytotoxic cell killing, wound healing, macrophage M2 polarization, Treg response, and a reduction in NFκB signaling, Th1, Th17 cell responses, pro-inflammatory cytokine production, platelet aggregation, inflammasome formation[221,222]. Eicosanoids (lipid-based signaling molecules) are critical in initiating and resolving inflammation. As inflammation progresses, eicosanoids switch from initial pro-inflammatory lipid mediators like prostaglandins and leukotrienes to pro-resolving lipid mediators like lipoxins, resolvins, and protectins. Higher lipoxin levels are associated with a lower risk of developing T2DM[223]. Lipoxin treatment reduced albuminuria, mesangial expansion, and collagen deposition and diminished established kidney disease, with evidence of preserved kidney function in a mouse model of DKD[224]. The lesser studied ω-3 fatty acid-derived mediators, resolvins, protectins, and maresins, also preserve kidney function and reduce inflammatory mediators in various models of kidney injury[225-228].
Pro-resolving mediators have emerged as therapeutic targets in numerous inflammatory diseases. The diabetic milieu with a relentless presence of pro-inflammatory inducers might explain the inefficient resolution of chronic low-grade inflammation. Pro-resolving mediator therapy holds promise for managing and even reversing DKD[222,229,230].
POSSIBILITIES
Comprehending the inflammatory processes associated with DKD will help detect it early and develop effective therapies to halt its progression and perhaps even reverse it. Therefore, mediators of inflammation implicated in the onset and progression of DKD are under study as diagnostic and prognostic biomarkers and potential therapeutic targets[18,76,96,184,231,232].
Biomarkers
The gold-standard biomarkers for identifying and classifying DKD are albuminuria and eGFR, focusing on kidney function. Pathogenic signaling and minor structural changes precede functional decline, which portrays the unmet need for novel diagnostic biomarkers[18,76,157]. Using machine learning algorithms on human transcriptomic data and mouse experiments, Zhong et al. identified DKD diagnostic markers related to oxidative stress and inflammation: tenascin C, peroxidasin, tissue inhibitor metalloproteinases 1, and tropomyosin[233]. Further comprehensive studies are required to test each protein for its potential. Table 1 summarizes some promising inflammation-related candidates.
Potential inflammation-related biomarkers of DKD
| Biomarker | Relevant findings | References |
| TNF-α | Serum TNF-α increases in DKD patients with increasing albuminuria DKD treatment suppresses urinary TNF-α | [186,234] |
| TNF-α receptors | Serum TNFR1 and TNFR2 levels predict renal functional decline in patients with T1DM and T2DM | [235-237] |
| MCP1/CCL2 | Urinary MCP1/CCL2 levels correlate with albuminuria and may or may not predict eGFR decline | [237-239] |
| SAA | SAA increases in DKD patients and correlates with disease progression | [35] |
| IL6 | Urinary IL6 levels indicate DKD severity Serum IL6 levels can predict atherosclerosis in DKD | [190] |
Therapy
The drugs used for diabetes and DKD management have anti-inflammatory properties [Table 2], which might partly explain their renoprotective effects[77,96,161,240-252]. Potential anti-inflammatory therapeutic strategies for DKD are in various stages of development. STAT3 inhibitors - nifuroxazide and S3I-201 - have shown promise in animal models[253,254]. STAT3-inhibitor Stattic ameliorates kidney injury in mouse models of Alport syndrome and lupus nephritis but remains to be tested for DKD[255,256]. Table 3 summarizes anti-inflammatory drugs for DKD therapy backed by clinical evidence. Phosphodiesterase-inhibitor pentoxifylline (FDA-approved for intermittent claudication) reduces eGFR decline, albuminuria, and urinary TNF-α in type 2 DKD[234]. Even if some of these get the final FDA approval, they will contribute significantly toward achieving improved cardio-renal-metabolic health of patients with DKD.
The drugs comprising the current standard of care for DKD have anti-inflammatory effects
| Class of drugs | Mechanism of action | Anti-inflammatory effects | Renal effects | Adverse effects | References |
| ACE inhibitors | Inhibit conversion of angiotensin I to angiotensin II | Increase expression of TNF-α, IL6, CCL2/MCP1, and NFκB in glomeruli and tubular cells | Decreases hyperfiltration and albuminuria, decreases BP | Cough, angioedema, hyperkalemia | [240] |
| Angiotensin receptor blockers | Inhibit angiotensin effects by blocking the angiotensin II type 1 receptor | Same as ACE inhibitors | Decreases albuminuria, renoprotective, decreases BP | Hyperkalemia | [240] |
| Metformin | Enhances AMP kinase activity | Regulates tenascin C and TLR4/NFκB signaling | Slows the progression of vascular complications of DM, including DKD | Lactic acidosis in advanced DKD | [241] |
| SGLT2 inhibitors | Inhibit SGLT2 in proximal tubules | Reduce cellular stressors and direct anti-inflammatory effects | Decreases plasma glucose levels, diuresis, natriuresis, reduces BP, lowers proteinuria, renoprotective | Urinary infections, ketoacidosis | [77,242-247] |
| GLP1 receptor agonists | Stimulate GLP1 receptors | Reduce TNF levels | Reduces proteinuria, slows the progression of CKD, Induces weight loss | Nausea, vomiting, ketoacidosis, pancreatitis, medullary thyroid cancer | [77,161,248,249] |
| Finerenone | Non-steroidal selective aldosterone receptor antagonist | Reduce cytokine-mediated oxidative stress and immune cell infiltration | Renoprotective, mild diuresis, anti-hypertensive, reduces albuminuria and slows GFR decline | Hyperkalemia, worsening of kidney function in advanced CKD | [96,250-252] |
Potential anti-inflammatory drugs for DKD therapy
| Name | Mechanism of action | Renal effects | Status | References |
| Bardoxolone | Nrf-2 inducer (NFκB inhibitor) | Improves GFR | Phase 3 | [257-263] |
| Pirfenidone | TGF-β inhibitor | Increases GFR | Phase 2 | [264] |
| Baricitinib | JAK1/JAK2 inhibitor | Reduces proteinuria | Phase 2 | [110] |
| PF-04634817 | CCR2/5 antagonist | Modest reduction of proteinuria | Phase 2 | [265] |
| CCX140-B | CCR2 inhibitor | Reduces proteinuria | Phase 2 | [266] |
| ASP8232 | VCAM1 inhibitor | Reduces albuminuria | Phase 2 | [267] |
CONCLUSION
While DKD has been traditionally viewed as a non-inflammatory microvascular disease, it is now evident that inflammation plays an integral part in its onset and progression. Chronic presence of non-infectious factors continuously induces PRRs in immune and kidney cells, activating inflammatory pathways, causing immune cell infiltration, and progressive damage to renal function and architecture. The pathogenesis of DKD is complex and heterogeneous. The patients with DKD are also a heterogeneous population, and some groups within them will benefit from treatment targeting inflammation more than others. As we begin to actualize early biomarkers and rely on more than the current markers of kidney function, we can detect DKD earlier and potentially arrest the progression.
DECLARATIONS
Acknowledgments
We acknowledge Dr. Subash Kairamkonda for his help in preparing and revising the manuscript and Woirhaye Research Endowment for making this publication possible. All figures were created with BioRender.com.
Authors’ contributions
Contributed substantially to developing the manuscript with literature search, writing, and revisions: Chatterjee A, Prabhakar S
Contributed to several sections and figures which were later reviewed by the other authors: Tumarin J
Availability of data and materials
Not applicable.
Financial support and sponsorship
This work was supported by the Woirhaye Research Endowment.
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. IDF Diabetes Atlas. 2021. Available from: https://www.diabetesatlas.org [Last accessed on 5 Jul 2024].
2. Pavkov ME, Miyamoto Y. Diabetes and kidney disease. In: Magliano DJ, Boyko EJ, Genitsaridi I, Piemonte L, Riley P, Salpea P, editors. IDF diabetes atlas reports. Brussels, Belgium: International Diabetes Federation; 2023.
3. Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG. DEMAND investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 2006;69:2057-63.
4. The International Diabetes Federation (IDF) and the International Society of Nephrology (ISN). Renewing the fight: a call to action on diabetes and chronic kidney disease. 2023. Available from: https://idf.org/what-we-do/advocacy/resources/?search=Renewing+the+fight%3A+a+call+to+action+on+diabetes+and+chronic+kidney+disease&type=&audience= [Last accessed on 5 Jul 2024].
6. Pahwa R, Goyal A, Jialal I. Chronic inflammation. 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493173/ [Last accessed on 5 Jul 2024].
7. Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci 2000;67:291-300.
8. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997;40:1286-92.
9. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-34.
10. Woroniecka KI, Park AS, Mohtat D, Thomas DB, Pullman JM, Susztak K. Transcriptome analysis of human diabetic kidney disease. Diabetes 2011;60:2354-69.
11. Fu S, Cheng Y, Wang X, et al. Identification of diagnostic gene biomarkers and immune infiltration in patients with diabetic kidney disease using machine learning strategies and bioinformatic analysis. Front Med 2022;9:918657.
12. Guo W, Song Y, Sun Y, et al. Systemic immune-inflammation index is associated with diabetic kidney disease in type 2 diabetes mellitus patients: evidence from NHANES 2011-2018. Front Endocrinol 2022;13:1071465.
13. Sheng X, Qiu C, Liu H, et al. Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease. Proc Natl Acad Sci USA 2020;117:29013-24.
14. Liu W, Zheng S, Du X. Association of systemic immune-inflammation index and systemic inflammation response index with diabetic kidney disease in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes 2024;17:517-31.
15. Fu J, Sun Z, Wang X, et al. The single-cell landscape of kidney immune cells reveals transcriptional heterogeneity in early diabetic kidney disease. Kidney Int 2022;102:1291-304.
16. Zhang X, Chao P, Zhang L, et al. Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease. Front Immunol 2023;14:1030198.
17. Wilson PC, Wu H, Kirita Y, et al. The single-cell transcriptomic landscape of early human diabetic nephropathy. Proc Natl Acad Sci USA 2019;116:19619-25.
18. Alicic RZ, Johnson EJ, Tuttle KR. Inflammatory mechanisms as new biomarkers and therapeutic targets for diabetic kidney disease. Adv Chronic Kidney Dis 2018;25:181-91.
19. Niewczas MA, Pavkov ME, Skupien J, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med 2019;25:805-13.
20. Wolkow PP, Niewczas MA, Perkins B, et al. Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol 2008;19:789-97.
21. Araújo LS, da Silva MV, da Silva CA, et al. Analysis of serum inflammatory mediators in type 2 diabetic patients and their influence on renal function. PLoS One 2020;15:e0229765.
22. Winter L, Wong LA, Jerums G, et al. Use of readily accessible inflammatory markers to predict diabetic kidney disease. Front Endocrinol 2018;9:225.
23. Mottl AK, Tuttle KR, Bakris GL. Diabetic kidney disease: manifestations, evaluation, and diagnosis. 2024. Available from: https://medilib.ir/uptodate/show/119881 [Last accessed on 5 Jul 2024].
24. Ekinci EI, Jerums G, Skene A, et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care 2013;36:3620-6.
25. Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I. High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes 2008;57:3090-8.
26. Iskender H, Yenice G, Terim Kapakin KA, et al. Effects of high fructose diet on lipid metabolism and the hepatic NF-κB/ SIRT-1 pathway. Biotech Histochem 2022;97:30-8.
27. Pasqualli T, Chaves PEE, da Veiga Pereira L, Serpa ÉA, Flávio Souza de Oliveira L, Mansur Machado M. The use of fructose as a sweetener. Is it a safe alternative for our immune system? J Food Biochem 2020;44:e13496.
28. Fajstova A, Galanova N, Coufal S, et al. Diet rich in simple sugars promotes pro-inflammatory response via gut microbiota alteration and TLR4 signaling. Cells 2020;9:2701.
29. Al-Khafaji AB, Tohme S, Yazdani HO, Miller D, Huang H, Tsung A. Superoxide induces neutrophil extracellular trap formation in a TLR-4 and NOX-dependent mechanism. Mol Med 2016;22:621-31.
30. Gupta A, Singh K, Fatima S, et al. Neutrophil extracellular traps promote NLRP3 inflammasome activation and glomerular endothelial dysfunction in diabetic kidney disease. Nutrients 2022;14:2965.
31. Lewko B, Stepinski J. Hyperglycemia and mechanical stress: targeting the renal podocyte. J Cell Physiol 2009;221:288-95.
32. Thomas MC, Brownlee M, Susztak K, et al. Diabetic kidney disease. Nat Rev Dis Primers 2015;1:15018.
33. Shahzad K, Fatima S, Khawaja H, et al. Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease. Kidney Int 2022;102:766-79.
34. Nishad R, Mukhi D, Kethavath S, et al. Podocyte derived TNF-α mediates monocyte differentiation and contributes to glomerular injury. FASEB J 2022;36:e22622.
35. Anderberg RJ, Meek RL, Hudkins KL, et al. Serum amyloid a and inflammation in diabetic kidney disease and podocytes. Lab Invest 2015;95:697.
36. Song C, Wang S, Fu Z, et al. IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis. Cell Death Dis 2022;13:340.
37. Zeng H, Pan T, Zhan M, et al. Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response. Signal Transduct Target Ther 2022;7:303.
38. Fu Y, Wang X, Zhang L, Ren Y, Hao L. Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway in diabetic kidney disease. Biochem Biophys Res Commun 2022;614:63-9.
39. Panzer U, Thaiss F, Zahner G, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int 2001;59:1762-9.
40. Harindhanavudhi T, Parks A, Mauer M, Caramori ML. Podocyte structural parameters do not predict progression to diabetic nephropathy in normoalbuminuric type 1 diabetic patients. Am J Nephrol 2015;41:277-83.
41. Liu B, Miao X, Shen J, et al. USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses. Int Immunopharm 2023;124:110877.
42. Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH, de Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Front Physiol 2018;9:114.
43. Kaiser N, Sasson S, Feener EP, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes 1993;42:80-9.
44. Devaraj S, Cheung AT, Jialal I, et al. Evidence of increased inflammation and microcirculatory abnormalities in patients with type 1 diabetes and their role in microvascular complications. Diabetes 2007;56:2790-6.
45. Lafuente N, Matesanz N, Azcutia V, et al. The deleterious effect of high concentrations of D-glucose requires pro-inflammatory preconditioning. J Hypertens 2008;26:478-85.
46. Azcutia V, Abu-Taha M, Romacho T, et al. Inflammation determines the pro-adhesive properties of high extracellular d-glucose in human endothelial cells in vitro and rat microvessels in vivo. PLoS One 2010;5:e10091.
47. Peiró C, Romacho T, Azcutia V, et al. Inflammation, glucose, and vascular cell damage: the role of the pentose phosphate pathway. Cardiovasc Diabetol 2016;15:82.
50. Xu C, Ha X, Yang S, Tian X, Jiang H. Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms. Front Endocrinol 2023;14:1232790.
51. Wu J, Wang Z, Cai M, et al. GPR56 promotes diabetic kidney disease through eNOS regulation in glomerular endothelial cells. Diabetes 2023;72:1652-63.
52. Zhan M, Usman IM, Sun L, Kanwar YS. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J Am Soc Nephrol 2015;26:1304-21.
53. Rabbani N, Thornalley PJ. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int 2018;93:803-13.
54. Kumar SV, Kulkarni OP, Mulay SR, et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol 2015;26:2399-413.
55. Saffarzadeh M, Juenemann C, Queisser MA, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 2012;7:e32366.
56. Lim BJ, Yang JW, Zou J, et al. Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. Kidney Int 2017;92:1395-403.
57. Long YS, Zheng S, Kralik PM, Benz FW, Epstein PN. Impaired albumin uptake and processing promote albuminuria in OVE26 diabetic mice. J Diabetes Res 2016;2016:8749417.
58. Zeni L, Norden AGW, Cancarini G, Unwin RJ. A more tubulocentric view of diabetic kidney disease. J Nephrol 2017;30:701-17.
59. Tang SC, Chan LY, Leung JC, et al. Bradykinin and high glucose promote renal tubular inflammation. Nephrol Dial Transplant 2010;25:698-710.
60. Wu XQ, Zhang DD, Wang YN, Tan YQ, Yu XY, Zhao YY. AGE/RAGE in diabetic kidney disease and ageing kidney. Free Radic Biol Med 2021;171:260-71.
61. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression. Horm Metab Res 2012;44:891-5.
62. Klessens CQF, Zandbergen M, Wolterbeek R, et al. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant 2017;32:1322-9.
63. Nguyen D, Ping F, Mu W, Hill P, Atkins RC, Chadban SJ. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology 2006;11:226-31.
64. Verzola D, Milanesi S, Viazzi F, et al. Enhanced myostatin expression and signalling promote tubulointerstitial inflammation in diabetic nephropathy. Sci Rep 2020;10:6343.
65. Kang HM, Ahn SH, Choi P, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 2015;21:37-46.
66. Cai T, Ke Q, Fang Y, et al. Sodium-glucose cotransporter 2 inhibition suppresses HIF-1α-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice. Cell Death Dis 2020;11:390.
67. Feng L, Gu C, Li Y, Huang J. High glucose promotes CD36 expression by upregulating peroxisome proliferator-activated receptor γ levels to exacerbate lipid deposition in renal tubular cells. Biomed Res Int 2017;2017:1414070.
68. Sun H, Yuan Y, Sun Z. Update on mechanisms of renal tubule injury caused by advanced glycation end products. Biomed Res Int 2016;2016:5475120.
69. Yang W, Luo Y, Yang S, et al. Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease. Clin Sci 2018;132:2407-22.
70. Kono T, Maimaituxun G, Tanabe H, et al. Role of perirenal adiposity in renal dysfunction among CKD individuals with or without diabetes: a Japanese cross-sectional study. BMJ Open Diabetes Res Care 2024;12:e003832.
71. Xu S, Ma J, Zheng Y, et al. Para-perirenal fat thickness is associated with reduced glomerular filtration rate regardless of other obesity-related indicators in patients with type 2 diabetes mellitus. PLoS One 2023;18:e0293464.
72. Arnalich F, Hernanz A, López-Maderuelo D, et al. Enhanced acute-phase response and oxidative stress in older adults with type II diabetes. Horm Metab Res 2000;32:407-12.
73. Prabhakar S, Starnes J, Shi S, Lonis B, Tran R. Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 2007;18:2945-52.
74. Jha JC, Ho F, Dan C, Jandeleit-Dahm K. A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes. Clin Sci 2018;132:1811-36.
75. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002;106:2067-72.
76. Hojs R, Ekart R, Bevc S, Hojs N. Markers of inflammation and oxidative stress in the development and progression of renal disease in diabetic patients. Nephron 2016;133:159-62.
77. Winiarska A, Knysak M, Nabrdalik K, Gumprecht J, Stompór T. Inflammation and oxidative stress in diabetic kidney disease: the targets for SGLT2 inhibitors and GLP-1 receptor agonists. Int J Mol Sci 2021;22:10822.
78. Jha JC, Banal C, Chow BS, Cooper ME, Jandeleit-Dahm K. Diabetes and kidney disease: role of oxidative stress. Antioxid Redox Signal 2016;25:657-84.
79. Jha JC, Dai A, Garzarella J, et al. Independent of renox, NOX5 promotes renal inflammation and fibrosis in diabetes by activating ROS-sensitive pathways. Diabetes 2022;71:1282-98.
80. Forbes JM, Coughlan MT, Cooper ME. Role of oxidative stress in diabetic nephropathy. In: Prabhakar SS, editor. Advances in pathogenesis of diabetic nephropathy. New York: Nova Science Publishers, Inc.; 2012. pp.199-218.
81. Casalena GA, Yu L, Gil R, et al. The diabetic microenvironment causes mitochondrial oxidative stress in glomerular endothelial cells and pathological crosstalk with podocytes. Cell Commun Signal 2020;18:105.
82. Erekat NS. Programmed cell death in diabetic nephropathy: a review of apoptosis, autophagy, and necroptosis. Med Sci Monit 2022;28:e937766.
83. Wang H, Liu D, Zheng B, et al. Emerging role of ferroptosis in diabetic kidney disease: molecular mechanisms and therapeutic opportunities. Int J Biol Sci 2023;19:2678-94.
84. Park E, Chung SW. ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis 2019;10:822.
85. Luo EF, Li HX, Qin YH, et al. Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World J Diabetes 2021;12:124-37.
86. Li S, Zheng L, Zhang J, Liu X, Wu Z. Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy. Free Radic Biol Med 2021;162:435-49.
87. Wang YH, Chang DY, Zhao MH, Chen M. Glutathione peroxidase 4 is a predictor of diabetic kidney disease progression in type 2 diabetes mellitus. Oxid Med Cell Longev 2022;2022:2948248.
88. Zhou W, Liu Y, Hu Q, Zhou J, Lin H. The landscape of immune cell infiltration in the glomerulus of diabetic nephropathy: evidence based on bioinformatics. BMC Nephrol 2022;23:303.
89. Wang J, Chen W, Chen S, Yue G, Hu Y, Xu J. Landscape of infiltrating immune cells and related genes in diabetic kidney disease. Clin Exp Nephrol 2024;28:181-91.
90. Rockey DC, Bell PD, Hill JA. Fibrosis - a common pathway to organ injury and failure. N Engl J Med 2015;373:95-6.
91. Huang R, Fu P, Ma L. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduct Target Ther 2023;8:129.
92. Falke LL, Gholizadeh S, Goldschmeding R, Kok RJ, Nguyen TQ. Diverse origins of the myofibroblast - implications for kidney fibrosis. Nat Rev Nephrol 2015;11:233-44.
93. Bohle A, Mackensen-Haen S, von Gise H, et al. The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis. Pathol Res Pract 1990;186:135-44.
94. Wang D, Yin L, Chen R, et al. Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease. Front Med 2022;9:1018298.
95. Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011;7:327-40.
96. Liu C, Yang M, Li L, et al. A glimpse of inflammation and anti-inflammation therapy in diabetic kidney disease. Front Physiol 2022;13:909569.
97. Pérez-Morales RE, Del Pino MD, Valdivielso JM, Ortiz A, Mora-Fernández C, Navarro-González JF. Inflammation in diabetic kidney disease. Nephron 2019;143:12-6.
98. Mezzano S, Aros C, Droguett A, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 2004;19:2505-12.
99. Wang Y, Zhu X, Yuan S, et al. TLR4/NF-κB signaling induces GSDMD-related pyroptosis in tubular cells in diabetic kidney disease. Front Endocrinol 2019;10:603.
100. Foresto-Neto O, Albino AH, Arias SCA, et al. NF-κB system is chronically activated and promotes glomerular injury in experimental type 1 diabetic kidney disease. Front Physiol 2020;11:84.
101. Lu TC, Wang ZH, Feng X, et al. Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy. Kidney Int 2009;76:63-71.
102. Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 1998;275:C1640-52.
103. Marrero MB, Banes-Berceli AK, Stern DM, Eaton DC. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol Renal Physiol 2006;290:F762-8.
104. Liu Y, Wang W, Zhang J, Gao S, Xu T, Yin Y. JAK/STAT signaling in diabetic kidney disease. Front Cell Dev Biol 2023;11:1233259.
105. Bao NN, Kong DY, Zhu D, Hao LR. Influence of overexpression of SOCS2 on cells of DN rat. Asian Pac J Trop Med 2015;8:583-9.
106. Chen D, Liu Y, Chen J, et al. JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes. Eur J Pharmacol 2021;902:174121.
107. Yu L, Zhang Y, Zhang H, Li Y. SOCS3 overexpression inhibits advanced glycation end product-induced EMT in proximal tubule epithelial cells. Exp Ther Med 2017;13:3109-15.
108. Berthier CC, Zhang H, Schin M, et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 2009;58:469-77.
109. Huang F, Wang Q, Guo F, et al. FoxO1-mediated inhibition of STAT1 alleviates tubulointerstitial fibrosis and tubule apoptosis in diabetic kidney disease. EBioMedicine 2019;48:491-504.
110. Tuttle KR, Brosius FC 3rd, Adler SG, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a phase 2 randomized controlled clinical trial. Nephrol Dial Transplant 2018;33:1950-9.
111. El-Kady MM, Naggar RA, Guimei M, Talaat IM, Shaker OG, Saber-Ayad M. Early renoprotective effect of ruxolitinib in a rat model of diabetic nephropathy. Pharmaceuticals 2021;14:608.
112. Zhang Y, Jin D, Kang X, et al. Signaling pathways involved in diabetic renal fibrosis. Front Cell Dev Biol 2021;9:696542.
113. Tian L, Shao X, Xie Y, et al. Kidney injury molecule-1 is elevated in nephropathy and mediates macrophage activation via the mapk signalling pathway. Cell Physiol Biochem 2017;41:769-83.
114. Wu J, Mei C, Vlassara H, Striker GE, Zheng F. Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells. Am J Physiol Renal Physiol 2009;297:F1622-31.
115. Ma FY, Flanc RS, Tesch GH, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol 2007;18:472-84.
116. Chan ED, Riches DW. IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 2001;280:C441-50.
117. Sakai N, Wada T, Furuichi K, et al. Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy. Am J Kidney Dis 2005;45:54-65.
118. Fujita H, Omori S, Ishikura K, Hida M, Awazu M. ERK and p38 mediate high-glucose-induced hypertrophy and TGF-beta expression in renal tubular cells. Am J Physiol Renal Physiol 2004;286:F120-6.
119. Woznowski MP, Potthoff SA, Königshausen E, et al. Inhibition of p38 MAPK decreases hyperglycemia-induced nephrin endocytosis and attenuates albuminuria. J Mol Med 2022;100:781-95.
120. Kang SW, Adler SG, Lapage J, Natarajan R. p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli. Kidney Int 2001;60:543-52.
121. Reddy MA, Adler SG, Kim YS, et al. Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells. Am J Physiol Renal Physiol 2002;283:F985-94.
122. Tan SM, Snelson M, Østergaard JA, Coughlan MT. The complement pathway: new insights into immunometabolic signaling in diabetic kidney disease. Antioxid Redox Signal 2022;37:781-801.
123. Flyvbjerg A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol 2017;13:311-8.
125. Østergaard JA, Thiel S, Lajer M, et al. Increased all-cause mortality in patients with type 1 diabetes and high-expression mannan-binding lectin genotypes: a 12-year follow-up study. Diabetes Care 2015;38:1898-903.
126. Tserga A, Saulnier-Blache JS, Palamaris K, et al. Complement cascade proteins correlate with fibrosis and inflammation in early-stage type 1 diabetic kidney disease in the Ins2Akita mouse model. Int J Mol Sci 2024;25:1387.
127. Hovind P, Hansen TK, Tarnow L, et al. Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes 2005;54:1523-7.
128. Kelly KJ, Liu Y, Zhang J, Dominguez JH. Renal C3 complement component: feed forward to diabetic kidney disease. Am J Nephrol 2015;41:48-56.
129. Uesugi N, Sakata N, Nangaku M, et al. Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: glycoxidation-mediated local complement activation. Am J Kidney Dis 2004;44:224-38.
130. Gora IM, Ciechanowska A, Ladyzynski P. NLRP3 inflammasome at the interface of inflammation, endothelial dysfunction, and type 2 diabetes. Cells 2021;10:314.
131. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477-89.
132. Wu M, Yang Z, Zhang C, et al. Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism 2021;118:154748.
133. Jridi I, Canté-Barrett K, Pike-Overzet K, Staal FJT. Inflammation and Wnt signaling: target for immunomodulatory therapy? Front Cell Dev Biol 2020;8:615131.
134. Liu J, Xiao Q, Xiao J, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 2022;7:3.
135. Bose M, Almas S, Prabhakar S. Wnt signaling and podocyte dysfunction in diabetic nephropathy. J Investig Med 2017;65:1093-101.
136. Baulida J, Díaz VM, Herreros AG. Snail1: a transcriptional factor controlled at multiple levels. J Clin Med 2019;8:757.
137. Wang B, Ding C, Ding X, et al. WNT1-inducible signaling pathway protein 1 regulates kidney inflammation through the NF-κB pathway. Clin Sci 2022;136:29-44.
138. Li X, Wen J, Dong Y, et al. Wnt5a promotes renal tubular inflammation in diabetic nephropathy by binding to CD146 through noncanonical Wnt signaling. Cell Death Dis 2021;12:92.
139. Pereira C, Schaer DJ, Bachli EB, Kurrer MO, Schoedon G. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 2008;28:504-10.
140. Li SS, Sun Q, Hua MR, et al. Targeting the Wnt/β-catenin signaling pathway as a potential therapeutic strategy in renal tubulointerstitial fibrosis. Front Pharmacol 2021;12:719880.
141. Zhou L, Li Y, Hao S, et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. J Am Soc Nephrol 2015;26:107-20.
142. Kuusniemi AM, Lapatto R, Holmberg C, Karikoski R, Rapola J, Jalanko H. Kidneys with heavy proteinuria show fibrosis, inflammation, and oxidative stress, but no tubular phenotypic change. Kidney Int 2005;68:121-32.
143. Zhang H, Pan B, Huang W, et al. IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β-catenin pathway. Immunology 2023;168:120-34.
144. You H, Lei P, Andreadis ST. JNK is a novel regulator of intercellular adhesion. Tissue Barriers 2013;1:e26845.
146. Cohen C, Mhaidly R, Croizer H, et al. WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease. Nat Commun 2024;15:743.
147. Liang J, Zhou Y, Zhang N, et al. The phosphorylation of the Smad2/3 linker region by nemo-like kinase regulates TGF-β signaling. J Biol Chem 2021;296:100512.
148. Chung AC, Dong Y, Yang W, Zhong X, Li R, Lan HY. Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs. Mol Ther 2013;21:388-98.
149. Yu L, Border WA, Huang Y, Noble NA. TGF-beta isoforms in renal fibrogenesis. Kidney Int 2003;64:844-56.
150. Murakami K, Takemura T, Hino S, Yoshioka K. Urinary transforming growth factor-beta in patients with glomerular diseases. Pediatr Nephrol 1997;11:334-6.
151. Kayhan M, Vouillamoz J, Rodriguez DG, et al. Intrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease. Nat Commun 2023;14:3236.
152. Melo Z, Palomino J, Franco-acevedo A, et al. Pharmacological blockade of TGF-beta reduces renal interstitial fibrosis in a chronic ischemia-reperfusion animal model. Drugs Drug Cand 2023;2:137-47.
153. Voelker J, Berg PH, Sheetz M, et al. Anti-TGF-β1 antibody therapy in patients with diabetic nephropathy. J Am Soc Nephrol 2017;28:953-62.
154. Qi W, Chen X, Zhang Y, et al. High glucose induces macrophage inflammatory protein-3 alpha in renal proximal tubule cells via a transforming growth factor-beta 1 dependent mechanism. Nephrol Dial Transplant 2007;22:3147-53.
155. Levéen P, Larsson J, Ehinger M, et al. Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 2002;100:560-8.
156. Neelisetty S, Alford C, Reynolds K, et al. Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells. Kidney Int 2015;88:503-14.
157. Jung SW, Moon JY. The role of inflammation in diabetic kidney disease. Korean J Intern Med 2021;36:753-66.
159. Li B, Leung JCK, Chan LYY, Yiu WH, Tang SCW. A global perspective on the crosstalk between saturated fatty acids and toll-like receptor 4 in the etiology of inflammation and insulin resistance. Prog Lipid Res 2020;77:101020.
160. Santana MFM, Lira ALA, Pinto RS, et al. Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis. Lipids Health Dis 2020;19:205.
161. Sourris KC, Ding Y, Maxwell SS, et al. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int 2024;105:132-49.
162. Klanke B, Cordasic N, Hartner A, Schmieder RE, Veelken R, Hilgers KF. Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension. Nephrol Dial Transplant 2008;23:3456-63.
163. Muthaian R, Pakirisamy RM, Parasuraman S, Raveendran R. Hypertension influences the exponential progression of inflammation and oxidative stress in streptozotocin-induced diabetic kidney. J Pharmacol Pharmacother 2016;7:159-64.
164. Yang CC, Liao PH, Cheng YH, Chien CY, Cheng KH, Chien CT. Diabetes associated with hypertension exacerbated oxidative stress-mediated inflammation, apoptosis and autophagy leading to erectile dysfunction in rats. J Chin Med Assoc 2022;85:346-57.
165. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010;10:826-37.
166. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw 2018;18:e27.
167. Ren L, Blanchette JB, White LR, et al. Soluble fibronectin induces chemokine gene expression in renal tubular epithelial cells. Kidney Int 2005;68:2111-20.
168. Xie Q, Zhang M, Mao X, et al. Matrix protein tenascin-C promotes kidney fibrosis via STAT3 activation in response to tubular injury. Cell Death Dis 2022;13:1044.
169. Liu T, Li Q, Jin Q, et al. Targeting HMGB1: a potential therapeutic strategy for chronic kidney disease. Int J Biol Sci 2023;19:5020-35.
170. Guarda NS, Bollick YS, de Carvalho JAM, Premaor MO, Comim FV, Moresco RN. High serum uric acid is associated with tubular damage and kidney inflammation in patients with type 2 diabetes. Dis Markers 2019;2019:6025804.
171. Jung SW, Kim SM, Kim YG, Lee SH, Moon JY. Uric acid and inflammation in kidney disease. Am J Physiol Renal Physiol 2020;318:F1327-40.
172. Lin M, Yiu WH, Wu HJ, et al. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol 2012;23:86-102.
173. Mudaliar H, Pollock C, Komala MG, Chadban S, Wu H, Panchapakesan U. The role of toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Renal Physiol 2013;305:F143-54.
174. Kaur H, Chien A, Jialal I. Hyperglycemia induces toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am J Physiol Renal Physiol 2012;303:F1145-50.
175. Verzola D, Cappuccino L, D'Amato E, et al. Enhanced glomerular toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int 2014;86:1229-43.
176. Devaraj S, Tobias P, Kasinath BS, Ramsamooj R, Afify A, Jialal I. Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy. Arterioscler Thromb Vasc Biol 2011;31:1796-804.
177. Kim SM, Kim YG, Kim DJ, et al. Inflammasome-independent role of NLRP3 mediates mitochondrial regulation in renal injury. Front Immunol 2018;9:2563.
178. Tanji N, Markowitz GS, Fu C, et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 2000;11:1656-66.
179. Sanajou D, Ghorbani Haghjo A, Argani H, Aslani S. AGE-RAGE axis blockade in diabetic nephropathy: current status and future directions. Eur J Pharmacol 2018;833:158-64.
180. Hansen TK, Gall MA, Tarnow L, et al. Mannose-binding lectin and mortality in type 2 diabetes. Arch Intern Med 2006;166:2007-13.
181. Hansen TK, Forsblom C, Saraheimo M, et al. Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes. Diabetologia 2010;53:1517-24.
182. Gedebjerg A, Bjerre M, Kjaergaard AD, et al. Mannose-binding lectin and risk of cardiovascular events and mortality in type 2 diabetes: a danish cohort study. Diabetes Care 2020;43:2190-8.
183. Zhou ZF, Jiang L, Zhao Q, et al. Roles of pattern recognition receptors in diabetic nephropathy. J Zhejiang Univ Sci B 2020;21:192-203.
184. Donate-Correa J, Ferri CM, Sánchez-Quintana F, et al. Inflammatory cytokines in diabetic kidney disease: pathophysiologic and therapeutic implications. Front Med 2020;7:628289.
185. Araújo LS, Torquato BGS, da Silva CA, et al. Renal expression of cytokines and chemokines in diabetic nephropathy. BMC Nephrol 2020;21:308.
186. Moriwaki Y, Yamamoto T, Shibutani Y, et al. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism 2003;52:605-8.
187. Kader Mahmoud RA, Abou El-Ezz SA, Hegazy AS. Increased serum levels of interleukin-18 in patients with diabetic nephropathy. Ital J Biochem 2004;53:73-81.
188. Wong CK, Ho AW, Tong PC, et al. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. Clin Exp Immunol 2007;149:123-31.
189. Kado S, Nagase T, Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol 1999;36:67-72.
190. Shikano M, Sobajima H, Yoshikawa H, et al. Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with diabetic nephropathy. Nephron 2000;85:81-5.
191. Milas O, Gadalean F, Vlad A, et al. Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients. J Diabetes Complications 2020;34:107479.
192. Vesey DA, Cheung C, Cuttle L, Endre Z, Gobe G, Johnson DW. Interleukin-1beta stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-beta-dependent mechanism. J Lab Clin Med 2002;140:342-50.
193. Navarro JF, Mora-Fernández C. The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev 2006;17:441-50.
194. Min D, Lyons JG, Bonner J, Twigg SM, Yue DK, McLennan SV. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol 2009;297:F1229-37.
195. Fang Y, Wang B, Pang B, et al. Exploring the relations of NLR, hsCRP and MCP-1 with type 2 diabetic kidney disease: a cross-sectional study. Sci Rep 2024;14:3211.
196. Siddiqui K, Joy SS, Al-Rubeaan K. Association of urinary monocyte chemoattractant protein-1 (MCP-1) and kidney injury molecule-1 (KIM-1) with risk factors of diabetic kidney disease in type 2 diabetes patients. Int Urol Nephrol 2019;51:1379-86.
197. Kikuchi Y, Ikee R, Hemmi N, et al. Fractalkine and its receptor, CX3CR1, upregulation in streptozotocin-induced diabetic kidneys. Nephron Exp Nephrol 2004;97:e17-25.
198. Shimizu K, Furuichi K, Sakai N, et al. Fractalkine and its receptor, CX3CR1, promote hypertensive interstitial fibrosis in the kidney. Hypertens Res 2011;34:747-52.
199. Song KH, Park J, Park JH, Natarajan R, Ha H. Fractalkine and its receptor mediate extracellular matrix accumulation in diabetic nephropathy in mice. Diabetologia 2013;56:1661-9.
200. Seron D, Cameron JS, Haskard DO. Expression of VCAM-1 in the normal and diseased kidney. Nephrol Dial Transplant 1991;6:917-22.
201. Sugimoto H, Shikata K, Hirata K, et al. Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes 1997;46:2075-81.
202. Chen Q, Huang J, Gong W, et al. MRTF-A mediated FN and ICAM-1 expression in AGEs-induced rat glomerular mesangial cells via activating STAT5. Mol Cell Endocrinol 2018;460:123-33.
203. Ina K, Kitamura H, Okeda T, et al. Vascular cell adhesion molecule-1 expression in the renal interstitium of diabetic KKAy mice. Diabetes Res Clin Pract 1999;44:1-8.
204. Rubio-Guerra AF, Vargas-Robles H, Lozano Nuevo JJ, Escalante-Acosta BA. Correlation between circulating adhesion molecule levels and albuminuria in type-2 diabetic hypertensive patients. Kidney Blood Press Res 2009;32:106-9.
206. Peruchetti DB, Silva-Filho JL, Silva-Aguiar RP, et al. IL-4 receptor α chain protects the kidney against tubule-interstitial injury induced by albumin overload. Front Physiol 2020;11:172.
207. Novianti Y, Nur'aeny N. Exploring interleukin-10 levels in diabetes patients with and without oral diseases: a systematic review. J Inflamm Res 2024;17:541-52.
208. Huang J, Tan Q, Tai N, et al. IL-10 deficiency accelerates type 1 diabetes development via modulation of innate and adaptive immune cells and gut microbiota in BDC2.5 NOD mice. Front Immunol 2021;12:702955.
209. Barry JC, Shakibakho S, Durrer C, et al. Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in type 2 diabetes. Sci Rep 2016;6:21244.
210. Jin Y, Liu R, Xie J, Xiong H, He JC, Chen N. Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model. Lab Invest 2013;93:801-11.
211. Naing C, Htet NH, Basavaraj AK, Nalliah S. An association between IL-10 promoter polymorphisms and diabetic nephropathy: a meta-analysis of case-control studies. J Diabetes Metab Disord 2018;17:333-43.
212. Fan X, Zhang X, Liu LC, et al. Interleukin-10 attenuates renal injury after myocardial infarction in diabetes. J Investig Med 2022;70:1233-42.
213. Widjaja AA, Viswanathan S, Shekeran SG, et al. Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease. Nat Commun 2022;13:7497.
214. Widjaja AA, Cook SA. The pathobiology of IL-11 in kidney disease: from epithelial cell to fibroblast and back again. Am J Pathol 2023;193:1910-3.
215. Prasad R, Suchetha A, Lakshmi P, Darshan MB, Apoorva SM, Ashit GB. Interleukin-11 - its role in the vicious cycle of inflammation, periodontitis and diabetes: a clinicobiochemical cross-sectional study. J Indian Soc Periodontol 2015;19:159-63.
216. Stanya KJ, Jacobi D, Liu S, et al. Direct control of hepatic glucose production by interleukin-13 in mice. J Clin Invest 2013;123:261-71.
217. Martínez-Reyes CP, Gómez-Arauz AY, Torres-Castro I, et al. Serum levels of interleukin-13 increase in subjects with insulin resistance but do not correlate with markers of low-grade systemic inflammation. J Diabetes Res 2018;2018:7209872.
218. Gu L, Liu H, Liu X, Zeng X, Lei Z, Wan X. The relationship between interleukin-4 levels and cardiovascular events in patients with chronic kidney disease. Risk Manag Healthc Policy 2020;13:2371-7.
219. Liu C, Qin L, Ding J, et al. Group 2 innate lymphoid cells participate in renal fibrosis in diabetic kidney disease partly via TGF-β1 signal pathway. J Diabetes Res 2019;2019:8512028.
220. Ortiz-Muñoz G, Lopez-Parra V, Lopez-Franco O, et al. Suppressors of cytokine signaling abrogate diabetic nephropathy. J Am Soc Nephrol 2010;21:763-72.
221. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008;8:349-61.
222. Panigrahy D, Gilligan MM, Serhan CN, Kashfi K. Resolution of inflammation: an organizing principle in biology and medicine. Pharmacol Ther 2021;227:107879.
223. Wang S, Qian X, Shen C, et al. The protective effects of lipoxin A4 on type 2 diabetes mellitus: a Chinese prospective cohort study. Front Endocrinol 2023;14:1109747.
224. Brennan EP, Mohan M, McClelland A, et al. Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease. J Am Soc Nephrol 2018;29:1437-48.
225. Qu X, Zhang X, Yao J, Song J, Nikolic-Paterson DJ, Li J. Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J Pathol 2012;228:506-19.
226. Tang S, Gao C, Long Y, et al. Maresin 1 mitigates high glucose-induced mouse glomerular mesangial cell injury by inhibiting inflammation and fibrosis. Mediators Inflamm 2017;2017:2438247.
227. Bathina S, Gundala NKV, Rhenghachar P, et al. Resolvin D1 ameliorates nicotinamide-streptozotocin-induced type 2 diabetes mellitus by its anti-inflammatory action and modulating PI3K/Akt/mTOR pathway in the brain. Arch Med Res 2020;51:492-503.
228. Duffield JS, Hong S, Vaidya VS, et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol 2006;177:5902-11.
229. Brennan E, Kantharidis P, Cooper ME, Godson C. Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function. Nat Rev Nephrol 2021;17:725-39.
230. Vartak T, Godson C, Brennan E. Therapeutic potential of pro-resolving mediators in diabetic kidney disease. Adv Drug Deliv Rev 2021;178:113965.
231. Hofherr A, Williams J, Gan LM, Söderberg M, Hansen PBL, Woollard KJ. Targeting inflammation for the treatment of diabetic kidney disease: a five-compartment mechanistic model. BMC Nephrol 2022;23:208.
232. Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int 2023;103:282-96.
233. Zhong M, Zhu E, Li N, et al. Identification of diagnostic markers related to oxidative stress and inflammatory response in diabetic kidney disease by machine learning algorithms: evidence from human transcriptomic data and mouse experiments. Front Endocrinol 2023;14:1134325.
234. Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol 2015;26:220-9.
235. Niewczas MA, Gohda T, Skupien J, et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 2012;23:507-15.
236. Gohda T, Niewczas MA, Ficociello LH, et al. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 2012;23:516-24.
237. Agarwal R, Duffin KL, Laska DA, Voelker JR, Breyer MD, Mitchell PG. A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease. Nephrol Dial Transplant 2014;29:2293-302.
238. Tam FW, Riser BL, Meeran K, Rambow J, Pusey CD, Frankel AH. Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy. Cytokine 2009;47:37-42.
239. Verhave JC, Bouchard J, Goupil R, et al. Clinical value of inflammatory urinary biomarkers in overt diabetic nephropathy: a prospective study. Diabetes Res Clin Pract 2013;101:333-40.
240. Ruiz-Ortega M, Ruperez M, Lorenzo O, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl 2002;62:S12-22.
241. Zhou Y, Ma XY, Han JY, et al. Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/
242. Lee CT, Lin KD, Hsieh CF, Wang JY. SGLT2 inhibitor canagliflozin alleviates high glucose-induced inflammatory toxicity in BV-2 microglia. Biomedicines 2023;12:36.
243. Cai A, Shen J, Yang X, et al. Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels. Front Immunol 2023;14:1205834.
244. Gohari S, Ismail-Beigi F, Mahjani M, et al. The effect of sodium-glucose co-transporter-2 (SGLT2) inhibitors on blood interleukin-6 concentration: a systematic review and meta-analysis of randomized controlled trials. BMC Endocr Disord 2023;23:257.
245. Packer M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis. Circulation 2022;146:1383-405.
246. Tuttle KR. Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors. J Clin Invest 2023;133:e167700.
247. Sheng W, Yu J, Zhang H, Zhang J. Empagliflozin attenuates inflammation levels in autoimmune myocarditis through the STAT3 pathway and macrophage phenotype transformation. Mol Immunol 2024;167:43-52.
248. von Scholten BJ, Persson F, Rosenlund S, et al. Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: a sub-analysis of a randomized, placebo-controlled, double-blind, crossover trial. Diabetes Obes Metab 2017;19:901-5.
249. Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011;54:965-78.
250. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020;383:2219-29.
251. Epstein M, Kovesdy CP, Clase CM, Sood MM, Pecoits-Filho R. Aldosterone, mineralocorticoid receptor activation, and CKD: a review of evolving treatment paradigms. Am J Kidney Dis 2022;80:658-66.
252. Lv R, Xu L, Che L, Liu S, Wang Y, Dong B. Cardiovascular-renal protective effect and molecular mechanism of finerenone in type 2 diabetic mellitus. Front Endocrinol 2023;14:1125693.
253. Said E, Zaitone SA, Eldosoky M, Elsherbiny NM. Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats. Chem Biol Interact 2018;281:111-20.
254. Pang M, Ma L, Gong R, et al. A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy. Kidney Int 2010;78:257-68.
255. Edwards LJ, Mizui M, Kyttaris V. Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clin Immunol 2015;158:221-30.
256. Yokota T, Omachi K, Suico MA, et al. STAT3 inhibition attenuates the progressive phenotypes of alport syndrome mouse model. Nephrol Dial Transplant 2018;33:214-23.
257. Hong DS, Kurzrock R, Supko JG, et al. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012;18:3396-406.
258. Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365:327-36.
259. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369:2492-503.
260. Chin MP, Bakris GL, Block GA, et al. Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol 2018;47:40-7.
261. Avula UMR, Harris L, Hassanein M. Bardoxolone for CKD: the paradox of confusion and dogma. Kidney360 2022;3:1955-60.
262. Nangaku M, Kanda H, Takama H, Ichikawa T, Hase H, Akizawa T. Randomized clinical trial on the effect of bardoxolone methyl on GFR in diabetic kidney disease patients (TSUBAKI study). Kidney Int Rep 2020;5:879-90.
263. Nangaku M, Takama H, Ichikawa T, et al. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study. Nephrol Dial Transplant 2023;38:1204-16.
264. Sharma K, Ix JH, Mathew AV, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 2011;22:1144-51.
265. Gale JD, Gilbert S, Blumenthal S, et al. Effect of PF-04634817, an Oral CCR2/5 chemokine receptor antagonist, on albuminuria in adults with overt diabetic nephropathy. Kidney Int Rep 2018;3:1316-27.
266. de Zeeuw D, Bekker P, Henkel E, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol 2015;3:687-96.
Cite This Article
Open AccessHow to Cite
Chatterjee, A.; Tumarin J.; Prabhakar S. Role of inflammation in the progression of diabetic kidney disease. Vessel. Plus. 2024, 8, 28. http://dx.doi.org/10.20517/2574-1209.2024.21
Download Citation
Export Citation File:
Type of Import
Tips on Downloading Citation
Citation Manager File Format
Type of Import
Direct Import: When the Direct Import option is selected (the default state), a dialogue box will give you the option to Save or Open the downloaded citation data. Choosing Open will either launch your citation manager or give you a choice of applications with which to use the metadata. The Save option saves the file locally for later use.
Indirect Import: When the Indirect Import option is selected, the metadata is displayed and may be copied and pasted as needed.
About This Article
Copyright
Data & Comments
Data
0
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.