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eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Lookup NU author(s): Dr Kathryn White


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Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS(-/-) mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS(-/-) mice, even though it inhibited glomerular capillary enlargement in both. In eNOS(-/-) mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS(-/-) mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS(-/-) glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.

Publication metadata

Author(s): Yuen DA, Stead BE, Zhang YL, White KE, Kabir MG, Thai K, Advani SL, Connelly KA, Takano T, Zhu L, Cox AJ, Kelly DJ, Gibson IW, Takahashi T, Harris RC, Advani A

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2012

Volume: 23

Issue: 11

Pages: 1810-1823

Print publication date: 31/10/2012

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology


DOI: 10.1681/ASN.2011121170


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Funder referenceFunder name
Clinician Scientist Award from the Heart and Stroke Foundation of Ontario
KRESCENT postdoctoral fellowship
Novo Nordisk Diabetes Innovation Award program
Physicians' Services Incorporated Foundation
Canadian Society of Transplantation postdoctoral fellowship
CIHR grants
Novo Nordisk Diabetes Innovation Award
OG-3-10-2949-AACanadian Diabetes Association