Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in
Diabetic Mice
Authors Hui John Zhao, Suwan Wang, Huifang Cheng, Ming-zhi Zhang, Takamune Takahashi,
Agnes B. Fogo, Matthew D. Breyer, and Raymond C. Harris
Submitted By Matthew Breyer on 8/30/2006
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2006
Date Published 10/1/2006
Volume : Pages 17 : 2664 - 2669
PubMed Reference 16971655
Abstract 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. In the present study, we
characterized the severity of DN in eNOS-/- mice backcrossed to C57BLKS/J db/db
mice. Although the severity of hyperglycemia was similar to C57BLKS/J db/db
mice, by 26 weeks, eNOS-/- C57BLKS/J db/db mice exhibited dramatic albuminuria,
arteriolar hyalinosis, increased GBM thickness, mesangial expansion,
mesangiolysis and focal segmental and early nodular glomerulosclerosis. Even
more remarkably, eNOS-/- C57BLKS db/db exhibited decreases in glomerular
filtration rates to levels less than 50% of that in eNOS+/+ C57BLKS db/db, as
confirmed by increased serum creatinine. In summary, eNOS deficient db/db mice
provide the most robust model of type II DM nephropathy that has been described
to date and support a role for deficient eNOS-derived nitric oxide production in
the pathogenesis of DN.


Nos3nitric oxide synthase 3, endothelial cell