Role of mTOR in podocyte function and diabetic nephropathy in humans and mice.
Authors Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mór A,
Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG,
Kretzler M, Wanke R, Pavenstädt H, Kerjaschki D, Cohen CD, Hall MN, Rüegg MA,
Inoki K, Walz G, Huber TB
Submitted By Matthias Kretzler on 12/10/2012
Status Published
Journal The Journal of clinical investigation
Year 2011
Date Published 6/1/2011
Volume : Pages 121 : 2197 - 2209
PubMed Reference 21606591
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.

Investigators with authorship
Matthias KretzlerUniversity of Michigan