Deficiency of endothelial nitric-oxide synthase confers susceptibility to
diabetic nephropathy in nephropathy-resistant inbred mice.
Authors Kanetsuna Y, Takahashi K, Nagata M, Gannon MA, Breyer MD, Harris RC, Takahashi T
Submitted By Takamune Takahashi on 11/6/2007
Status Published
Journal The American journal of pathology
Year 2007
Date Published 5/1/2007
Volume : Pages 170 : 1473 - 1484
PubMed Reference 17456755
Abstract Recent studies have implicated dysfunctional endothelial nitric-oxide synthase
(eNOS) as a common pathogenic pathway in diabetic vascular complications.
However, functional consequences are still incompletely understood. To determine
the role of eNOS-derived nitric oxide (NO) in diabetic nephropathy, we induced
diabetes in eNOS knockout (KO) and wild-type (WT) mice on the C57BL6 background,
using low-dose streptozotocin injection, and we investigated their glomerular
phenotype at up to 20 weeks of diabetes. Although the severity of hyperglycemia
in diabetic eNOS KO mice was similar to diabetic WT mice, diabetic eNOS KO mice
developed overt albuminuria, hypertension, and glomerular mesangiolysis, whereas
diabetic WT and nondiabetic control mice did not. Glomerular hyperfiltration was
also significantly reduced in diabetic eNOS KO mice. Electron micrographs from
diabetic eNOS KO mice revealed an injured endothelial morphology, thickened
glomerular basement membrane, and focal foot process effacement. Furthermore,
the anionic sites at glomerular endothelial barrier estimated by cationic
ferritin binding were reduced in diabetic eNOS KO mice. In aggregate, these
results demonstrate that deficiency of eNOS-derived NO causes glomerular
endothelial injury in the setting of diabetes and results in overt albuminuria
and glomerular mesangiolysis in nephropathy-resistant inbred mice. The findings
indicate a vital role for eNOS-derived NO in the pathogenesis of diabetic

Investigators with authorship
Matthew BreyerEli Lilly and Company
Raymond HarrisVanderbilt University
Takamune TakahashiVanderbilt University