How Diabetes Damages the Kidneys: Oxidative Stress, Inflammation and Emerging Biomarkers

Diabetic nephropathy, one of the most serious complications of type 2 diabetes, is the focus of a new open-access review published in Discover Molecules on 16 August 2026. The review, authored by Kuldip Vyas, Abu Sufiyan Chhipa, Ayush Chauhan and Snehal S. Patel, brings together the current understanding of how progressive kidney damage develops in diabetes, which biomarkers may signal that damage early, and which drugs are being explored to slow the disease. The authors frame diabetic nephropathy as a condition characterized by chronic albuminuria and progressive loss of renal function, driven by an intricate crosstalk between metabolic and inflammatory pathways.

The scale of the underlying problem is considerable. The review notes that diabetes affects around 537 million individuals globally, and that the International Diabetes Federation expects that figure to reach roughly 783 million by 2045. More than 25% of diabetic patients have chronic kidney disease, and an estimated 40% of people with diabetes develop chronic kidney disease during their lifetime. Patients with type 1 diabetes account for about a third of chronic kidney disease cases, while those with type 2 diabetes account for about half. The review also cites India’s diabetes prevalence of roughly 8–10% of the adult population, affecting around 77 million people.

Diabetic nephropathy progresses through distinct stages. At the initial stage, the glomerular basement membrane thickens while the glomerular filtration rate remains normal, albuminuria is absent and blood pressure is not yet elevated. A subsequent stage is marked by mild to severe mesangial expansion, followed by a third stage featuring glomerular damage with microalbuminuria, defined as 30 to 300 milligrams of albumin per day. The fourth stage is advanced diabetic glomerulosclerosis with evident tubulointerstitial and vascular lesions, and the end stage is total loss of kidney function with a glomerular filtration rate below 15 millilitres per minute per 1.73 square metres.

At the molecular level, the review places oxidative stress at the centre of the disease process. Hyperglycemia drives the overproduction of reactive oxygen species, which directly damage lipids, proteins and DNA in renal cells, producing pathological alterations in the glomeruli, renal tubules and interstitium. Oxidative stress also activates the inflammatory pathway through NF-κB signalling, which in turn promotes further production of reactive oxygen species, so that oxidative stress and inflammation mutually reinforce each other and perpetuate kidney damage. Mitochondria are particularly vulnerable: their unsaturated fatty acids are susceptible to attack by reactive oxygen species, leading to membrane lipid peroxidation, abnormal opening of the mitochondrial permeability transition pore, a fall in mitochondrial membrane potential, uncoupling of oxidative phosphorylation and a decline in ATP synthesis. In one cited study, the diabetic microenvironment caused mitochondrial dysfunction and mitochondrial superoxide release in glomerular endothelial cells, with mitochondrial DNA oxidation and biogenesis but without cell death, and the dysfunctional endothelial cells released factors that induced apoptosis in podocytes.

Several metabolic pathways amplify this damage. The polyol pathway, which normally metabolizes less than 3% of intracellular glucose, processes around 30% during hyperglycemia; aldose reductase upregulation then depletes NADPH, compromising antioxidant defenses and allowing reactive oxygen species to accumulate. Advanced glycation end products, formed by non-enzymatic reactions between reducing sugars and proteins, lipids and nucleic acids, increase during hyperglycemia; their crosslinking with collagen contributes to basement membrane thickening and impaired filtration, while their interaction with the receptor for AGEs generates further reactive oxygen species through NADPH oxidase activation. The hexosamine pathway, which under normal conditions converts only 2–5% of fructose-6-phosphate to glucosamine-6-phosphate, is upregulated in hyperglycemia, increasing transforming growth factor β expression and promoting basement membrane thickening, and GFAT overexpression increases NF-κB promoter activity in mesangial cells. Protein kinase C also contributes: diabetic PKCα-deficient mice did not develop albuminuria in one cited study, and PKC activates NADPH oxidase to generate reactive oxygen species.

Inflammation itself is a major driver of the disease. Immunohistochemistry of renal biopsies from patients with diabetic nephropathy showed significant increases in the cytokines and chemokines IL-6, IL-1β, IL-4 and eotaxin. Podocytes exposed to high glucose secrete IL-6, which promotes podocyte apoptosis and growth arrest. Serum and urinary TNF-α levels rise significantly in patients with diabetic nephropathy compared with healthy controls and patients with type 2 diabetes without nephropathy, and this elevation is negatively correlated with estimated glomerular filtration rate and positively correlated with the albumin-to-creatinine ratio. In experimental work, TNF-α blockade with an anti-TNF-α antibody protected Ins2(Akita) mice from renal injury, and macrophage-specific TNF-α deficiency protected streptozotocin-induced diabetic mice. TGF-β1 signalling promotes extracellular matrix formation by generating myofibroblasts from pericytes, resident fibroblasts, epithelial cells and endothelial cells, and drives epithelial-to-mesenchymal transition, a key process in renal fibrosis.

Against this backdrop, the review devotes substantial attention to biomarkers that may detect kidney injury earlier than albuminuria. Neutrophil gelatinase-associated lipocalin, a marker of tubular cell damage, is significantly elevated in the serum and urine of patients with diabetic nephropathy and in patients with type 2 diabetes and albuminuria compared with those with normoalbuminuria. Serum β2-microglobulin levels are closely related to disease progression, and urinary β2-microglobulin correlates positively with urinary albumin concentration. Kidney injury molecule 1, a transmembrane glycoprotein of proximal tubule epithelial cells, rises significantly in patients with type 2 diabetes and microalbuminuria, and serum KIM-1 is associated with lower estimated glomerular filtration rate. Serum homocysteine is elevated in patients with diabetic nephropathy compared with diabetic patients without nephropathy, and correlates with renal impairment evident as reduced glomerular filtration rate and increased albuminuria. β-trace protein, an endogenous glomerular filtration marker, is suggested as an early biomarker, with serum levels significantly higher in patients with type 2 diabetes even at urinary albumin-to-creatinine ratios below 30 milligrams per gram.

Further candidate biomarkers include urinary angiotensinogen, which was higher in diabetic patients with normoalbuminuria as well as micro- and macroalbuminuria compared with controls, suggesting that it appears before albuminuria and could serve for early detection; in another study it correlated with the urinary albumin-to-creatinine ratio and showed an inverse relation with estimated glomerular filtration rate. Osteopontin, a multiphosphorylated glycoprotein involved in inflammation and fibrosis, was elevated at baseline in patients with type 1 diabetes who later developed incident microalbuminuria and progressed to end-stage renal disease, and urinary osteopontin was higher in patients with microalbuminuria than in controls. Urinary exosomes, extracellular vesicles arising from podocytes, renal tubular epithelium and the genitourinary tract, showed upregulation of 14 miRNAs in patients with diabetic kidney disease compared with patients with type 2 diabetes and healthy controls, and the miRNA let-7c-5p was significantly upregulated in patients with diabetic nephropathy and correlated with estimated glomerular filtration rate and disease progression. Serum miR-638 and miR-192 were both reduced in patients with diabetic nephropathy, with miR-638 negatively correlated with urinary albumin excretion and positively correlated with renal function, and miR-192 negatively correlated with albuminuria.

On the therapeutic side, the review describes established oral hypoglycemic agents with renal protective effects. DPP-4 inhibitors, which increase GLP-1 and GIP levels by preventing their enzymatic inactivation, have shown favourable outcomes in attenuating the albumin-to-creatinine ratio in patients with type 2 diabetes, attributed to suppression of oxidative stress, inflammation, fibrosis and apoptosis. SGLT-2 inhibitors are described as a mainstay treatment for diabetic kidney disease; canagliflozin reduced albuminuria and loss of kidney function in patients with severe albuminuria, while empagliflozin reduced albuminuria in diabetic mice and inhibited inflammation, oxidative stress and fibrotic reactions in the kidneys of diabetic rats by blocking the AGE-RAGE signalling axis. Thiazolidinediones, PPAR-γ agonists, were associated with reduced urinary albumin and protein excretion in patients with type 2 diabetes and micro- and macroalbuminuria, and pioglitazone partially restored glomerular hyperfiltration-related parameters in OLETF rats. GLP-1 receptor agonists reduced the albumin-to-creatinine ratio in Spontaneously Diabetic Torii fatty rats, exenatide reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and increased albuminuria, and tirzepatide, a dual GIP/GLP-1 receptor agonist, is associated with reduced diabetic kidney disease risk.

The review also surveys novel drug classes still under exploration. The PDE5 inhibitor sildenafil diminished microalbuminuria in patients with type 2 diabetes, and in a later study PDE5 inhibition prevented diabetes-related hypertension and increases in the urine albumin-to-creatinine ratio with improved renal microcirculation, through induction of bone morphogenetic protein-7 via downregulation of miR-22; pentoxifylline, a non-specific phosphodiesterase inhibitor, has been reported to have antiproteinuric effects and to slow the loss of estimated glomerular filtration rate. Vitamin D deficiency is observed in patients with diabetic nephropathy, and calcitriol supplementation reduced inflammation and proteinuria in diabetic individuals with vitamin D deficiency. Pyridoxamine, a natural form of vitamin B6 that inhibits the formation of advanced glycation end products, improved the urinary albumin-to-creatinine ratio in KK-Ay/Ta mice and reduced kidney malondialdehyde, TNF-α and TGF-β1 gene expression and urine microalbumin in alloxan-induced diabetic rats. The endothelin receptor A antagonist avosentan reduced glomerulosclerosis, mesangial matrix accumulation and expression of VEGF, TGF-β and NF-κB genes in diabetic mice. The authors caution that because studies on these novel targets remain limited, there is a lack of understanding of their potential side effects, and they conclude that more studies are warranted to establish the proposed biomarkers for the diagnosis of diabetic nephropathy.

Subject of Research: Pathophysiological mechanisms, potential biomarkers and therapeutic interventions in diabetic nephropathy

Article Title: Pathophysiological mechanisms, potential biomarkers, and therapeutic interventions in diabetic nephropathy

Article References: Vyas, K., Chhipa, A. S., chauhan, A., & Patel, S. S. (2026). Pathophysiological mechanisms, potential biomarkers, and therapeutic interventions in diabetic nephropathy. Discover Molecules, 3(1), Article 29. https://doi.org/10.1007/s44345-026-00071-x

Image Credits: AI Generated

DOI: 10.1007/s44345-026-00071-x

Keywords: diabetic nephropathy, oxidative stress, inflammation, biomarkers, NGAL, KIM-1, SGLT-2 inhibitors, GLP-1 receptor agonists, advanced glycation end products, kidney disease, microRNAs, hyperglycemia