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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-06, Vol.121 (6), p.2197-2209
Main Authors: 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
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Adult
Age
Animals
Biomedical research
Carrier Proteins - genetics
Carrier Proteins - physiology
Diabetes
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - physiopathology
Diabetic nephropathies
Diabetic Nephropathies - pathology
Diabetic Nephropathies - physiopathology
Diabetic nephropathy
Disease
Disease Progression
Gene Dosage
Genetic Predisposition to Disease
Homeostasis
Humans
Kidney Glomerulus - pathology
Kidney Glomerulus - physiopathology
Kinases
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Mice, Transgenic
Multiprotein Complexes
Nephrosis, Lipoid - physiopathology
Phosphorylation
Podocytes - drug effects
Podocytes - pathology
Podocytes - physiology
Proteins
Proteins - genetics
Proteins - physiology
Proteinuria - etiology
Proteinuria - genetics
Proteinuria - physiopathology
Proteinuria - prevention & control
Rapamycin-Insensitive Companion of mTOR Protein
Regulatory-Associated Protein of mTOR
Sirolimus - therapeutic use
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - physiology
Trans-Activators - deficiency
Trans-Activators - genetics
Trans-Activators - physiology
Transcription Factors
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Description
Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci44774