title: Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice.
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. 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.
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, C-3121 MCN, Nashville, TN 37232, USA.
authors.forename: Hui John
authors.initials: HJ
authors.lastname: Zhao
authors.forename: Suwan
authors.initials: S
authors.lastname: Wang
authors.forename: Huifang
authors.initials: H
authors.lastname: Cheng
authors.forename: Ming-zhi
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency*
chemical_list: D052250:Nitric Oxide Synthase Type III