Diabetic nephropathy: Role of nitric oxide.

Abstract

Diabetic nephropathy (DN) is characterized by structural kidney alterations-including glomerular basement membrane thickening, mesangial expansion, tubulointerstitial fibrosis, and glomerular hypertrophy-alongside functional impairments such as reduced glomerular filtration rate (GFR) and albuminuria. DN progresses through five stages: pre-nephropathy, silent, incipient, overt nephropathy, and end-stage kidney disease (ESKD). Dysregulation of the nitric oxide synthase (NOS) pathway-including neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS)-has been increasingly implicated in DN pathogenesis. Evidence from preclinical models using NOS inhibitors and knockout mice, combined with human studies that identify NOS gene polymorphisms, supports this association. In early stages, hyperglycemia elevates GFR, driven by increased NO production from all three NOS isoforms. As the disease progresses, reduced eNOS-derived NO and persistent iNOS overexpression contribute to structural damage and a decline in GFR. NO donors have been shown to prevent early hyperfiltration and attenuate the subsequent decrease in GFR and renal injury characteristic of overt nephropathy. Thus, NO signaling plays a dual role in DN progression and represents a promising target for therapeutic intervention.