mTORC1 Activation in Podocytes Is a Critical Step in the Development of Diabetic Nephropathy in Mice

J Clin Invest. 2011 Jun;121(6):2181-96. doi: 10.1172/JCI44771. Epub 2011 May 23.

Abstract

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition-like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Differentiation
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / prevention & control
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation
  • Glomerular Basement Membrane / pathology
  • Glomerular Mesangium / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Multiprotein Complexes
  • Phosphorylation
  • Podocytes / drug effects
  • Podocytes / enzymology*
  • Podocytes / pathology
  • Podocytes / physiology
  • Protein Processing, Post-Translational
  • Proteins / antagonists & inhibitors
  • Proteins / physiology*
  • Regulatory-Associated Protein of mTOR
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • Proteins
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • nephrin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases
  • Sirolimus