A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Chih Hong Wang, Feng Li, Sylvia Hiller, Hyung Suk Kim, Nobuyo Maeda, Oliver Smithies, Nobuyuki Takahashi

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49 Citations (Scopus)


Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene (NOS3) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases in eNOS expression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS+/+, eNOS+/-, or eNOS-/- with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS+/- inbred females and heterozygous C57BL/6J eNOS+/- inbred males carrying the dominant Akita diabetogenic mutation Ins2C96Y/+. Whereas all C57BL/6J inbred eNOS-/- and eNOS+/- diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS-/- and eNOS+/- diabetic mice lived until killed at 7 mo. Heterozygous eNOS+/- diabetic mice expressed ∼35% eNOS mRNA in the kidney and ∼25% glomerular eNOS protein relative to their eNOS+/+ diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS+/+ Akita < eNOS+/- Akita < eNOS-/- Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy; Nos2 also increased. Surprisingly, however, decreased eNOS expression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with human NOS3 variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP.

Original languageEnglish
Pages (from-to)2070-2075
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Publication statusPublished - 2011 Feb 1


  • Diabetic complications
  • Heterozygotes

ASJC Scopus subject areas

  • General


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