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Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice

Hui John Zhao^*, Suwan Wang^*, Huifang Cheng^*, Ming-zhi Zhang^*, Takamune Takahashi^*, Agnes B. Fogo^*,, Matthew D. Breyer^* and Raymond C. Harris^*

^* Division of Nephrology and Hypertension, Department of Medicine, and Department of Pathology, Vanderbilt University, Nashville, Tennessee

Address correspondence to: Dr. Raymond C. Harris, Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, C-3121 MCN, Nashville, TN 37232. Phone: 615-343-0030; Fax: 615-343-2675; E-mail: ray.harris{at}vanderbilt.edu

Functionally significant polymorphisms in endothelial nitric oxide synthase (eNOS) and reduced vascular eNOS activity have been associated with increased human diabetic nephropathy (DN), but the pathogenic role of eNOS deficiency in the development of DN has not yet been confirmed. This study characterizes the severity of DN in eNOS^–/– mice that were backcrossed to C57BLKS/J db/db mice. Although the severity of hyperglycemia was similar to C57BLKS/J db/db mice, by 26 wk, eNOS^–/– C57BLKS/J db/db mice exhibited dramatic albuminuria, arteriolar hyalinosis, increased glomerular basement membrane thickness, mesangial expansion, mesangiolysis, and focal segmental and early nodular glomerulosclerosis. Even more remarkable, eNOS^–/– C57BLKS db/db exhibited decreases in GFR to levels <50% of that in eNOS^+/+ C57BLKS db/db, as confirmed by increased serum creatinine. In summary, eNOS^–/– db/db mice provide the most robust model of type II DN that has been described to date and support a role for deficient eNOS-derived NO production in the pathogenesis of DN.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673