mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice
Ken Inoki, … , Roger C. Wiggins, Kun-Liang Guan
Ken Inoki, … , Roger C. Wiggins, Kun-Liang Guan
Published May 23, 2011
Citation Information: J Clin Invest. 2011;121(6):2181-2196. https://doi.org/10.1172/JCI44771.
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mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

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.

Authors

Ken Inoki, Hiroyuki Mori, Junying Wang, Tsukasa Suzuki, SungKi Hong, Sei Yoshida, Simone M. Blattner, Tsuneo Ikenoue, Markus A. Rüegg, Michael N. Hall, David J. Kwiatkowski, Maria P. Rastaldi, Tobias B. Huber, Matthias Kretzler, Lawrence B. Holzman, Roger C. Wiggins, Kun-Liang Guan

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Figure 1

mTORC1 activation in podocytes, and prevention of podocyte morphological changes by rapamycin treatment in db/db mice.

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mTORC1 activation in podocytes, and prevention of podocyte morphological...
(A) Foot process effacement in db/db mice is blocked by rapamycin (rapa). Glomeruli from mice at 25 weeks of age with the indicated genotypes were examined by TEM. Foot process width at the level of slit diaphragm was measured (100 foot processes/glomerulus, 4 glomeruli/mouse, 3 male mice/group); *P < 0.001 versus other groups, mean ± SEM. Rapamycin treatment (1 mg/kg, i.p. injection, 3 times/week) was performed from 8 to 25 weeks of age. Pod, podocyte. (B) mTORC1 activity is enhanced in the podocytes of diabetic animals. Double staining with anti–phospho-S6 and anti-WT1 antibodies was performed on frozen sections from mice of the indicated genotypes at 12 weeks of age. The arrows indicate enhanced phospho-S6 signal in the cytoplasm of db/db podocytes. Quantification of glomerular phospho-S6 (green) pixel density divided by glomerular area is shown. Data are expressed as fold induction (4 images per mouse, 3 male mice/group); *P < 0.001, mean ± SEM. Original magnification, ×13,500 (A); ×400 (B).