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

Godel, M. and Hartleben, B. and Herbach, N. and Liu, S. and Zschiedrich, S. and Lu, S. and Debreczeni-Mor, A. and Lindenmeyer, M. T. and Rastaldi, M. -P. and Hartleben, G. and Wiech, T. and Fornoni, A. and Nelson, R. G. and Kretzler, M. and Wanke, R. and Pavenstadt, H. and Kerjaschki, D. and Cohen, C. D. and Hall, M. N. and Ruegg, M. A. and Inoki, K. and Walz, G. and Huber, T. B.. (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. Journal of Clinical Investigation, 121 (6). pp. 2197-2209.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Hall, Michael N. and Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
e-ISSN:1558-8238
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:08 Nov 2017 14:24
Deposited On:14 Sep 2012 06:40

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