Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Lab Invest. 2008 May;88(5):515-28. doi: 10.1038/labinvest.2008.23. Epub 2008 Apr 7.


Functional consequences of impaired endothelial nitric oxide synthase (eNOS) activity causing organ-specific abnormalities on a diabetic setting are not completely understood. In this study, we extensively characterized a diabetic mouse model (lepr(db/db)) in which eNOS expression is genetically disrupted (eNOS-/-). The eNOS-/-/ lepr(db/db) double-knockout (DKO) mice developed obesity, hyperglycemia, hyperinsulinemia and hypertension. Analysis of tissues from DKO mice showed large islets in the pancreas and fat droplets in hepatocytes. Interestingly, the aorta was normal and atherogenic lesions were not observed. Abnormalities in the aorta including poor re-endothelialization and increased medial wall thickness were evident only in response to deliberate injury. In contrast, significant glomerular capillary damage in the kidney was identified, with DKO mice demonstrating a robust diabetic nephropathy similar to human disease. The vascular and renal impairments in DKO mice were pronounced despite lower fasting plasma glucose levels compared to lepr(db/db) mice, indicating that eNOS is a critical determinant of hyperglycemia-induced organ-specific complications and their severity in diabetes. Results provide the first evidence that absence of eNOS in diabetes has a greater deleterious effect on the renal microvasculature than on the larger aortic vessel. The DKO model may suggest novel therapeutic strategies to prevent both vascular and renal complications of diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Albuminuria / physiopathology
  • Animals
  • Aorta, Abdominal / injuries
  • Aorta, Abdominal / pathology
  • Body Weight
  • Creatinine / urine
  • Diabetes Complications*
  • Diabetes Mellitus / enzymology*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / physiopathology
  • Diabetic Angiopathies / etiology*
  • Diabetic Angiopathies / pathology
  • Diabetic Angiopathies / physiopathology
  • Endothelium, Vascular / pathology
  • Genotype
  • Hypertension / etiology
  • Insulin Resistance
  • Kidney / blood supply
  • Kidney / pathology
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Microcirculation
  • Nitric Oxide Synthase Type III / deficiency*


  • Creatinine
  • Nitric Oxide Synthase Type III