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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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Research Article Article has an altmetric score of 8

mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

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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 4

Rapamycin reverses established phenotypes in PcKOTsc1 mice.

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Rapamycin reverses established phenotypes in PcKOTsc1 mice.
(A and B) Ra...
(A and B) Rapamycin treatment ameliorated the established proteinuria in PcKOTsc1 mice. Proteinuria-positive 4-week-old PcKOTsc1 mice (n = 9) were treated with rapamycin for 2 and 6 weeks. The levels of urinary protein from 9 mice were tested at the indicated time points and visualized by Coomassie staining (n = 9) (A), and the ratio of albumin to creatinine concentration is shown (B). *P < 0.001 versus other groups, mean ± SEM, n = 9; note logarithmic scale for y axis. The ratios for 4- and 10-week-old wild-type mice are also shown. (C) H&E staining of renal tissue from 4-week-old untreated and 10-week-old treated PcKOTsc1 mice (rapamycin treatment for 6 weeks). Eosin-positive area in glomerulus was measured in 30 glomeruli from 4-week-old wild-type and PcKOTsc1 mice as well as 10-week-old treated PcKOTsc1 mice. *P < 0.001 versus other groups, no statistical significance between WT 4 weeks and KO with rapamycin 10 weeks, mean ± SEM, n = 3~5. (D) TEM analyses of 10-week-old PcKOTsc1 mice (rapamycin treatment for 6 weeks). Foot process width at the level of slit diaphragm was measured (20~50 foot processes/glomerulus, 3 glomeruli/mouse, 3 mice/group). *P < 0.001 versus other groups, mean ± SEM. (E) Scanning EM analyses of 6-week-old PcKOTsc1 mice (rapamycin treatment for 2 weeks). Representative glomerulus from 2 different rapamycin-treated PcKOTsc1 mice is shown. Original magnification, ×400 (C), ×7,900 (D), ×2,000 (E). Scale bars: 10 μm (top row); 2.5 μm (bottom row).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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