Chronic diabetic nephropathy: role of inducible nitric oxide synthase

Abstract

Nitric oxide (NO) is a multifunctional mediator that has been implicated in the short-term hemodynamic alterations that occur in acute streptozocin (STZ)-induced diabetes. We investigated the role of NO produced by inducible nitric oxide synthase (iNOS) in chronic STZ diabetic nephropathy. Diabetes was induced in C57BL/6 and iNOS knockout (KO) mice with two intraperitoneal injections of STZ, 100 mg/kg. Animals were maintained without insulin treatment for 40 weeks. There were no significant differences between the strains in blood urea nitrogen (BUN), serum creatinine or glucose concentration, or urinary protein excretion during the entire observation period. Urinary nitrite + nitrate excretion was significantly lower in iNOS KO mice compared to control animals at all time points; in C57 mice, urinary nitrite declined progressively with more prolonged duration of diabetes. Renal hypertrophy (kidney weight/body weight) was noted in both strains of mice. However, histopathological assessment of renal tissue specimens at 16 and 40 weeks demonstrated increased mesangial hypercellularity and expansion as well as more prominent tubulointerstitial fibrosis in iNOS KO versus C57 mice. These changes were accompanied by increased interstitial deposition of type I collagen at 16 and 40 weeks in iNOS KO mice. Glomerular basement membrane staining for type IV collagen was also increased at 40 weeks in diabetic iNOS KO mice. While iNOS protein was undetectable in any of the kidney specimens obtained from either strain, eNOS was present throughout the course of chronic STZ diabetes. Moreover, eNOS expression was significantly increased by approximately 40% at 16 and 40 weeks of observation in iNOS KO versus C57 mice. There was no difference in renal cortical malondialdehyde content between the strains early or late in the disease course. In time control animals, there was no evidence of renal histopathological damage in iNOS KO or C57 mice after 40 weeks. We conclude that iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic STZ nephropathy. This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.

Microvascular basement membranes in diabetes mellitus

“…Moreover, PDGF (B-chain) and its receptor appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy [49]. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy [50,51]. Finally, aminoguanidine, an inhibitor of the formation of AGE but with antioxidant properties, attenuates diabetic nephropathy, which is consistent with a role of oxygen radicals in the pathogenesis of this disease.…”

“…A thickened tubular basement membrane is part of diabetic tubulo-interstitial disease, and represents a better indicator of diabetic nephropathy than GBM thickening [51,52]. Expression of transcription factor NF-κB in proximal tubular epithelial cells was strongly increased in diabetic patients with nephropathy and high urinary levels of AGE-albumin and carboxymethyl-lysine (CML).…”

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…There are conflicting data on the role of iNOS in kidney injury in diabetes. Diabetes in iNOS knock-out mice was associated with worse renal injury as indicated by greater glomerular basement membrane thickening and worse tubule interstitial fibrosis, suggesting that iNOS is protective against diabetes-induced kidney injury (50). In contrast, kidney injury in streptozotocin-induced type 1 diabetes in rat was associated with an increase in iNOS expression, and sildenafil inhibited the iNOS increment and ameliorated kidney injury (51).…”

Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product–Induced Proliferation in Renal Fibroblasts

“…It has been shown that reduced NO may contribute to susceptibility to injury and renal fibrosis (18,19). iNOS-derived NO modulates glomerulosclerosis and tubulointerstitial fibrosis in chronic streptozotocin nephropathy (17). This action is probably a result of the direct actions of NO on the synthesis and degradation of extracellular matrix proteins.…”

“…Nitric oxide (NO) is a key mediator in renal physiology and pathology (17,18). Alterations of intrarenal NO synthesis play an important role in the pathogenesis and progression of diabetic complications (19).…”