Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice.

Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC
J Am Soc Nephrol. 2006 17 (10): 2664-9

PMID: 16971655 · PMCID: PMC4618687 · DOI:10.1681/ASN.2006070798

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.

MeSH Terms (12)

Albuminuria Animals Diabetes Mellitus, Type 2 Diabetic Nephropathies Disease Models, Animal Glomerular Filtration Rate Humans Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Nitric Oxide Synthase Type III

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