| Authors |
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
|
| Submitted By |
Raymond Harris on 1/30/2013 |
| Status |
Published |
| Journal |
Journal of the American Society of Nephrology : JASN |
| Year |
2012 |
| Date Published |
11/1/2012 |
| Volume : Pages |
23 : 1810 - 1823 |
| PubMed Reference |
22997257 |
| Abstract |
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.
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