Neutrophil activation, NETs formation, and inflammation in diabetic kidney disease: therapeutic perspectives.

Abstract

Diabetic kidney disease (DKD) represents the most common microvascular complication of diabetes mellitus and a principal driver of end-stage renal disease (ESRD). Recent studies have highlighted the central role of neutrophils in the pathogenesis and progression of DKD. Following aberrant activation, neutrophils infiltrate the renal interstitium, contributing to disease progression through the release of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, as well as the formation of neutrophil extracellular traps (NETs). Components associated with NETs, such as histones and myeloperoxidase (MPO), can directly activate renal inflammatory signaling cascades, thereby promoting tissue damage. Clinically, neutrophil-to-lymphocyte ratio (NLR) and neutrophil gelatinase-associated lipocalin (NGAL) serve as valuable biomarkers for the early detection and monitoring of DKD. Consequently, therapeutic strategies targeting neutrophil activation, NETs formation, and the associated inflammatory pathways are emerging as promising avenues for DKD treatment, including the use of PAD4 inhibitors and IL-1β blockers. Future research should continue to elucidate the intricate mechanisms governing NETs formation and resolution to facilitate the development of targeted therapies and the clinical translation of relevant biomarkers for DKD.