NETosis in diabetic kidney disease: Molecular mechanisms and therapeutic opportunities

Diabetic Kidney Disease (DKD) is a leading cause of end-stage renal failure, with limited therapeutic options beyond glycemic and blood pressure control. NETosis, is a unique form of neutrophil cell death where they extrude their nuclear material comprising of DNA-histone complexes and granular proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE) in the form of Neutrophil Extracellular Traps (NETs). Hyperglycemia-induced reactive oxygen species (ROS), calcium influx, activation of Protein-arginine deiminase type-4 (PAD4) and NADPH oxidases contribute to NETs formation in the diabetic milieu. Recent clinical investigations have identified that specific biomarkers of NETosis such as MPO-DNA complex, citrullinated histone (CitH3), and NE were elevated in DKD patients. NETosis exacerbates glomerular and tubular injury by promoting endothelial dysfunction, podocyte damage, and fibrotic remodeling. This review summarizes the molecular mechanisms linking NETosis to DKD pathogenesis, while highlighting emerging biomarkers of NETosis in diabetic patients and critically evaluate current therapeutic strategies such as PAD4 inhibitors, DNase therapies, and repurposed agents like metformin and vitamin D. Despite promising preclinical and clinical findings, translation of NETosis targeting therapies is hindered because most therapies fail to strike the balance between effective disease attenuation with preservation of innate immune defense mechanisms. Further research is essential to address patient heterogeneity, optimize clinical trial endpoints, and refine delivery strategies for targeted NETosis modulation in DKD. This review provides a comprehensive framework for understanding the translational potential and limitations of NETs-directed therapies, and guides towards targeted approaches to improve patient outcomes in DKD.