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.
| Original language | English |
|---|---|
| Pages (from-to) | 2197-2209 |
| Number of pages | 13 |
| Journal | Journal of Clinical Investigation |
| Volume | 121 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2011 |
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ASJC Scopus subject areas
- Medicine(all)
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Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. / Gödel, Markus; Hartleben, Björn; Herbach, Nadja; Liu, Shuya; Zschiedrich, Stefan; Lu, Shun; Debreczeni-Mór, Andrea; Lindenmeyer, Maja T.; Rastaldi, Maria Pia; Hartleben, Götz; Wiech, Thorsten; Fornoni, Alessia; Nelson, Robert G.; Kretzler, Matthias; Wanke, Rüdiger; Pavenstädt, Hermann; Kerjaschki, Dontscho; Cohen, Clemens D.; Hall, Michael N.; Rüegg, Markus A.; Inoki, Ken; Walz, Gerd; Huber, Tobias B.
In: Journal of Clinical Investigation, Vol. 121, No. 6, 01.06.2011, p. 2197-2209.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
AU - Gödel, Markus
AU - Hartleben, Björn
AU - Herbach, Nadja
AU - Liu, Shuya
AU - Zschiedrich, Stefan
AU - Lu, Shun
AU - Debreczeni-Mór, Andrea
AU - Lindenmeyer, Maja T.
AU - Rastaldi, Maria Pia
AU - Hartleben, Götz
AU - Wiech, Thorsten
AU - Fornoni, Alessia
AU - Nelson, Robert G.
AU - Kretzler, Matthias
AU - Wanke, Rüdiger
AU - Pavenstädt, Hermann
AU - Kerjaschki, Dontscho
AU - Cohen, Clemens D.
AU - Hall, Michael N.
AU - Rüegg, Markus A.
AU - Inoki, Ken
AU - Walz, Gerd
AU - Huber, Tobias B.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79957881425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79957881425&partnerID=8YFLogxK
U2 - 10.1172/JCI44774
DO - 10.1172/JCI44774
M3 - Article
C2 - 21606591
AN - SCOPUS:79957881425
VL - 121
SP - 2197
EP - 2209
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -