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(American Journal of Pathology. 2007;170:1473-1484.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060481

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

Yukiko Kanetsuna*{dagger}, Keiko Takahashi*, Michio Nagata{ddagger}, Maureen A. Gannon*, Matthew D. Breyer*, Raymond C. Harris* and Takamune Takahashi*

From the Department of Medicine,* Vanderbilt University School of Medicine, Nashville, Tennessee; the Department of Pathology,{dagger} Jikei University School of Medicine, Tokyo, Japan; and the Department of Pathology,{ddagger} Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

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 nephropathy.




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Copyright © 2007 by the American Society for Investigative Pathology.