Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Sumathy Mohan, Robert L. Reddick, Nicolas Musi, Diane A. Horn, Bo Yan, Thomas J. Prihoda, Mohan Natarajan, Sherry L. Abboud-Werner

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

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 (leprdb/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 leprdb/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.

Original languageEnglish (US)
Pages (from-to)515-528
Number of pages14
JournalLaboratory Investigation
Volume88
Issue number5
DOIs
StatePublished - May 2008

Keywords

  • Diabetes
  • Endothelial dysfunction
  • Micro- and macrovasculature
  • Nephropathy and vasculopathy
  • eNOS

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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