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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant

Yang Liu1,2, Martin Pejchinovski3, Xueqi Wang4

  • 1Institute of Physiology, University of Zürich, Zürich, Switzerland.

Scientific Reports
|April 5, 2018
PubMed

Insights

Targeting both mTOR and PI3K pathways with dual inhibitors may treat autosomal dominant polycystic kidney disease (ADPKD). This approach blocks pro-proliferative signals, normalizing kidney function and morphology in animal models.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) causes kidney cysts and eventual kidney failure.
  • Mammalian target of rapamycin (mTOR) inhibitors showed promise in animal models but failed in human trials for ADPKD.
  • mTOR inhibition can paradoxically up-regulate pro-proliferative signaling pathways like PI3K-Akt and PI3K-ERK in polycystic kidney disease (PKD).

Purpose of the Study:

  • To investigate the effects of dual mTOR and PI3K inhibition on ADPKD progression.
  • To determine if blocking these pathways can overcome the limitations of single-target mTOR inhibition.

Main Methods:

  • Utilized rat and mouse models of polycystic kidney disease (PKD).
  • Administered mTOR inhibitors and observed effects on signaling pathways.
  • Treated PKD models with a dual mTOR/PI3K inhibitor (NVP-BEZ235).
  • Assessed kidney morphology, function, proliferation, and fibrosis.

Main Results:

  • mTOR inhibitors alone led to the upregulation of pro-proliferative PI3K-Akt and PI3K-ERK signaling.
  • Dual mTOR/PI3K inhibition with NVP-BEZ235 effectively blocked these pro-proliferative signals.
  • NVP-BEZ235 treatment normalized kidney morphology and function in PKD models.
  • The dual inhibition strategy reduced cell proliferation and fibrosis.

Conclusions:

  • Dual PI3K/mTOR inhibition is a promising therapeutic strategy for ADPKD.
  • This approach effectively counteracts pro-proliferative signaling often induced by single-target mTOR inhibitors.
  • Targeting both pathways offers a potential new avenue for treating ADPKD and preventing kidney failure.

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