Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
Markus Gödel, … , Gerd Walz, Tobias B. Huber
Markus Gödel, … , Gerd Walz, Tobias B. Huber
Published May 23, 2011
Citation Information: J Clin Invest. 2011;121(6):2197-2209. https://doi.org/10.1172/JCI44774.
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Research Article

Role of mTOR in podocyte function and diabetic nephropathy in humans and mice

Abstract

Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.

Authors

Markus Gödel, Björn Hartleben, Nadja Herbach, Shuya Liu, Stefan Zschiedrich, Shun Lu, Andrea Debreczeni-Mór, Maja T. Lindenmeyer, Maria-Pia Rastaldi, Götz Hartleben, Thorsten Wiech, Alessia Fornoni, Robert G. Nelson, Matthias Kretzler, Rüdiger Wanke, Hermann Pavenstädt, Dontscho Kerjaschki, Clemens D. Cohen, Michael N. Hall, Markus A. Rüegg, Ken Inoki, Gerd Walz, Tobias B. Huber

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Figure 7

Podocyte-specific genetic inhibition of mTOR hyperactivation prevents progressive glomerular diseases.

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Podocyte-specific genetic inhibition of mTOR hyperactivation prevents pr...
(A) Schematic illustration of the generation of podocyte-specific Raptor heterozygous knockout mice (RaptorHet podocyte mice) to counteract mTORC1 hyperactivation. (B) Glomerular Raptor and pS6 levels in RaptorHet podocyte mice. (C) Densitometric analysis of Raptor and pS6 levels (n = 3 mice). (D) Reduced S6 phosphorylation in podocytes of diabetic RaptorHet podocyte mice in the STZ model (arrows indicate pS6 signal in podocytes). (E) Quantitative analysis of glomerular pS6 stained area in glomeruli (n = 3 mice each; **P < 0.001, ***P < 0.0001). (F) The RaptorHet podocyte genotype ameliorated the development of proteinuria in the STZ model (n = 11 control and n = 5 RaptorHet podocyte mice; *P < 0.05). (G) Histological analysis revealed reduced glomerulosclerosis and reduced mesangial matrix expansion in RaptorHet podocyte mice exposed to STZ (arrow indicates sclerosed glomerulus). (H) Glomerulosclerosis index (24) documenting ameliorated diabetic nephropathy in RaptorHet podocyte mice (n = 3 each; *P < 0.05) (I) There was a significant increase in glomerular mean mesangial volume in WT animals compared with RaptorHet podocyte mice after diabetes induction, with no significant difference in mean glomerular volume (n = 3 each; *P < 0.05). (J) Quantitative stereological analyses displayed a significantly increased mean podocyte volume in WT animals compared with RaptorHet podocyte mice after diabetes induction, with no significant difference in the number of podocytes per glomerulus (n = 3 each; *P < 0.05). (K) Ultrastructural analysis displayed increased podocyte volume in WT animals in the STZ model (arrows indicate podocytes; arrowhead indicates mesangial matrix expansion). Scale bars: 5 μm (D); 20 μm (G); 5 μm (K). Data are expressed as the mean ± SEM.