TY - JOUR
T1 - Diabetic eNOS knockout mice develop distinct macro- and microvascular complications
AU - Mohan, Sumathy
AU - Reddick, Robert L.
AU - Musi, Nicolas
AU - Horn, Diane A.
AU - Yan, Bo
AU - Prihoda, Thomas J.
AU - Natarajan, Mohan
AU - Abboud-Werner, Sherry L.
N1 - Funding Information:
This work was supported in part by National Institutes of Health (Grant no: 63032), Institutional ERC pilot project (118778) to SM; San Antonio Area Foundation (Grant nos. 118981 to SM and 120909 to MN); National Institutes of Health (AR 42306) and VA Merit Award to SW; American Diabetes Association to NM.
PY - 2008/5
Y1 - 2008/5
N2 - 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.
AB - 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.
KW - Diabetes
KW - Endothelial dysfunction
KW - Micro- and macrovasculature
KW - Nephropathy and vasculopathy
KW - eNOS
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U2 - 10.1038/labinvest.2008.23
DO - 10.1038/labinvest.2008.23
M3 - Article
C2 - 18391994
AN - SCOPUS:42549103718
VL - 88
SP - 515
EP - 528
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 5
ER -