eNOS deficiency predisposes podocytes to injury in diabetes.

Yuen DA, Stead BE, Zhang Y, 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
J Am Soc Nephrol. 2012 23 (11): 1810-23

PMID: 22997257 · PMCID: PMC3482727 · DOI:10.1681/ASN.2011121170

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.

MeSH Terms (19)

Albuminuria Angiotensin-Converting Enzyme Inhibitors Animals Capillaries Diabetes Mellitus, Experimental Diabetic Nephropathies Disease Models, Animal Glucose Humans Kidney Glomerulus Male Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type III Podocytes Renin-Angiotensin System rho GTP-Binding Proteins Vascular Endothelial Growth Factor Receptor-2

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