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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 3

PcKOTsc1 mice show proteinuria and podocyte loss.

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PcKOTsc1 mice show proteinuria and podocyte loss.
(A) Rapamycin treatmen...
(A) Rapamycin treatment prevents proteinuria in PcKOTsc1 mice. Scheme of administration of rapamycin is shown above. Urine (1 μl ) from mice of the indicated genotypes was subjected to SDS-PAGE with Coomassie blue staining (n = 6 each group). veh, vehicle. Asterisk indicates a leak of sample from lane 6. (B) Urinary albumin/creatinine ratio is shown. Urinary albumin and creatinine concentrations in 4-week-old mice were determined by ELISA. *P < 0.001 versus other groups, mean ± SEM, n = 6. Note logarithmic scale for the y axis. Rapamycin treatment was performed from 2 weeks of age as indicated in Figure 2A. (C) TEM analyses reveal abnormal foot process and GBM in PcKOTsc1 and wild-type mice. Representative TEM images of the indicated animals (3 mice/group) from 4 and 8 weeks of age are shown. Rapamycin treatment was as in Figure 2A. Original magnification, ×13,500 (top row), ×7,900 (bottom row). Scale bars: 1 μm. (D) Scanning EM analyses show abnormal podocyte in PcKOTsc1 mice, which was prevented by rapamycin treatment. Rapamycin treatment was as in Figure 2A. Original magnification, ×2,000. Scale bars: 5 μm (top row); 1.25 μm (bottom row). (E) Podocyte loss in PcKOTsc1 mice. The ratio (the number of WT1-positive cells/glomerular tuft area [μm2]) was determined in 15~30 glomeruli from the indicated animals. *P < 0.001 versus wild-type and/or KO with rapamycin treatment, mean ± SEM, n = 3–5 mice.

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

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