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mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

Ken Inoki1, Hiroyuki Mori, Junying Wang

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. inokik@umich.edu

The Journal of Clinical Investigation
|May 25, 2011
PubMed

Insights

mTOR complex 1 (mTORC1) activation in kidney podocytes drives diabetic nephropathy (DN) development. Inhibiting podocyte mTORC1 shows promise for preventing DN complications.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Diabetology

Background:

  • Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by podocyte dysfunction.
  • The precise molecular mechanisms underlying podocyte dysfunction in DN remain incompletely understood.

Purpose of the Study:

  • To investigate the role of mTOR complex 1 (mTORC1) in podocyte dysfunction and DN pathogenesis.
  • To explore the therapeutic potential of targeting podocyte mTORC1 activity in DN.

Main Methods:

  • Assessed mTORC1 activity in podocytes of diabetic animal models.
  • Utilized podocyte-specific genetic manipulation (PcKOTsc1 ablation) to activate mTORC1 in nondiabetic mice.
  • Examined DN features, podocyte structure, and endoplasmic reticulum (ER) stress.
  • Investigated the effect of reducing ER stress using chemical chaperones.
  • Reduced podocyte-specific mTORC1 in diabetic animals to assess DN development.

Main Results:

  • Enhanced mTORC1 activity was observed in podocytes of diabetic animals.
  • Podocyte-specific mTORC1 activation mimicked key DN features, including podocyte loss and proteinuria.
  • mTORC1 activation led to mislocalization of slit diaphragm proteins and an epithelial-mesenchymal transition-like switch.
  • ER stress was enhanced in podocytes with abnormal mTORC1 activation.
  • Reducing ER stress mitigated podocyte damage and loss.
  • Genetic reduction of podocyte mTORC1 suppressed DN development in diabetic animals.

Conclusions:

  • Podocyte mTORC1 activation is a critical factor in the pathogenesis of diabetic nephropathy.
  • Targeting mTORC1 activity in podocytes represents a potential therapeutic strategy for preventing DN.

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