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

J Clin Invest. 2011 Jun;121(6):2197-209. doi: 10.1172/JCI44774. Epub 2011 May 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Nephropathies / pathology*
  • Diabetic Nephropathies / physiopathology
  • Disease Progression
  • Gene Dosage
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • Mice, Transgenic
  • Multiprotein Complexes
  • Nephrosis, Lipoid / physiopathology
  • Podocytes / drug effects
  • Podocytes / pathology
  • Podocytes / physiology*
  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Crtc2 protein, mouse
  • Multiprotein Complexes
  • Proteins
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Trans-Activators
  • Transcription Factors
  • rictor protein, mouse
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus