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

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
Journal of Clinical Investigation 2011, 121 (6): 2197-209
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.

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