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Inhibition of MTOR disrupts autophagic flux in podocytes

Davide P Cinà1, Tuncer Onay, Aarti Paltoo

  • 1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada.

Journal of the American Society of Nephrology : JASN
|December 24, 2011
PubMed

Insights

Mammalian target of rapamycin (MTOR) inhibitors can cause kidney problems like proteinuria. Disruption of the autophagic pathway in podocytes may explain this side effect.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin (MTOR) inhibitors are used for immunosuppression and cancer treatment.
  • Proteinuria is a known side effect of MTOR inhibitors, but its mechanism is unclear.

Purpose of the Study:

  • To investigate the role of MTOR in podocyte function and its link to proteinuria.
  • To elucidate the mechanism behind MTOR inhibitor-induced proteinuria.

Main Methods:

  • Generated mice with podocyte-specific knockout of the Mtor gene.
  • Analyzed podocyte morphology, autophagosome markers (LC3), and mitochondrial integrity.
  • Treated human podocytes with the MTOR inhibitor rapamycin.

Main Results:

  • Mice with Mtor knockout in podocytes developed proteinuria and renal failure.
  • Podocytes showed accumulation of autophagosomes, autophagolysosomes, and damaged mitochondria.
  • Rapamycin treatment induced autophagosome accumulation in human podocytes.

Conclusions:

  • MTOR signaling is crucial for maintaining podocyte homeostasis.
  • Disruption of the autophagic pathway in podocytes contributes to MTOR inhibitor-associated proteinuria.
  • Targeting the autophagic pathway may offer therapeutic strategies for managing this side effect.

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