1. ¹Department of Pathology, The University of Texas Health Science Center, San Antonio, TX, USA
2. ²Department of Medicine, The University of Texas Health Science Center, San Antonio, TX, USA
3. ³Department of Otolaryngology Head & Neck Surgery, The University of Texas Health Science Center, San Antonio, TX, USA

Correspondence: Dr Sumathy Mohan, PhD, Assistant Professor, Department of Pathology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. E-mail: mohan@uthscsa.edu

Received 6 November 2007; Revised 11 January 2008; Accepted 18 January 2008; Published online 7 April 2008.

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 (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.