| Authors |
Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T,
Rüegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman
LB, Wiggins RC, Guan KL
|
| Submitted By |
Matthias Kretzler on 2/22/2012 |
| Status |
Published |
| Journal |
The Journal of clinical investigation |
| Year |
2011 |
| Date Published |
6/1/2011 |
| Volume : Pages |
121 : 2181 - 2196 |
| PubMed Reference |
21606597 |
| Abstract |
Diabetic nephropathy (DN) is among the most lethal complications that occur in
type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical
event associated with proteinuria and glomerulosclerosis in glomerular diseases
including DN. However, molecular mechanisms of podocyte dysfunction in the
development of DN are not well understood. Here we have shown that activity of
mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was
enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1
activation induced by ablation of an upstream negative regulator (PcKOTsc1)
recapitulated many DN features, including podocyte loss, glomerular basement
membrane thickening, mesangial expansion, and proteinuria in nondiabetic young
and adult mice. Abnormal mTORC1 activation caused mislocalization of slit
diaphragm proteins and induced an epithelial-mesenchymal transition-like
phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of
ER stress with a chemical chaperone significantly protected against both the
podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic
reduction of podocyte-specific mTORC1 in diabetic animals suppressed the
development of DN. These results indicate that mTORC1 activation in podocytes is
a critical event in inducing DN and suggest that reduction of podocyte mTORC1
activity is a potential therapeutic strategy to prevent DN.
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