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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-51059

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

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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.


145 citations in Web of Science®
151 citations in Scopus®
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227 downloads since deposited on 17 Nov 2011
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Deposited On:17 Nov 2011 09:25
Last Modified:05 Apr 2016 15:06
Publisher:American Society for Clinical Investigation
Publisher DOI:10.1172/JCI44774.
PubMed ID:21606591

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