Abstract: Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and the leading global cause of end-stage renal disease. While chronic hyperglycemia and classic metabolic pathways such as protein kinase C activation, advanced glycation end product (AGE) accumulation, and renin–angiotensin system overactivity elucidate many features of DKD, they do not fully account for its complex inflammatory pathology. Recent studies have highlighted neutrophil extracellular trap (NET) formation, or NETosis, as a critical mechanism linking metabolic stress to immune dysregulation in DKD. NETosis is a specialized form of programmed cell death in neutrophils that releases web-like chromatin structures decorated with histones, elastase, and myeloperoxidase. Although these structures function as protective barriers against pathogens, they become pathogenic when dysregulated. In the diabetic milieu, hyperglycemia, advanced glycation end products (AGEs), protein kinase C signaling, lipid abnormalities, and pro-inflammatory cytokines all promote excessive NETosis. Once formed, NETs drive renal injury by inducing endothelial dysfunction, podocyte and tubular epithelial cell damage, macrophage activation, and profibrotic signaling, thereby accelerating inflammation, fibrosis, and renal decline. Therapeutic strategies targeting NETosis are emerging, including inhibitors of PAD4, NADPH oxidase, and neutrophil elastase, as well as NET-degrading agents such as DNase I and histone-neutralizing compounds. Classical antidiabetic drugs, notably metformin and GLP-1 receptor agonists, also show potential in modulating NET formation. Collectively, these insights position NETosis as both a biomarker and a therapeutic target in DKD, offering novel opportunities to mitigate diabetes-associated renal complications. Keywords: diabetic kidney disease, kidney injury, neutrophil extracellular traps, NETosis, inflammation, therapeutic targets
Wang et al. (2026) studied this question.