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Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease

Zlata Novalic1, Annemieke M van der Wal, Wouter N Leonhard

  • 1Department of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands.

Journal of the American Society of Nephrology : JASN
|February 21, 2012
PubMed

Insights

High-dose mTOR inhibitors, but not low doses, effectively treat polycystic kidney disease (PKD) in mice when started early. Conventional sirolimus doses are insufficient for inhibiting mTOR in kidney cysts.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin (mTOR) inhibition shows promise in animal models of polycystic kidney disease (PKD).
  • Clinical trials in autosomal dominant PKD patients have yielded inconclusive results regarding mTOR inhibitor efficacy.
  • Treatment timing and drug dosage may explain discrepancies in mTOR inhibitor effectiveness for PKD.

Purpose of the Study:

  • To investigate the impact of varying sirolimus doses (low vs. high) on mTOR activity and renal cystic disease in Pkd1-mutant mouse models.
  • To determine if early-stage treatment is more effective than late-stage treatment for PKD using mTOR inhibitors.
  • To assess the correlation between mTOR activity levels and the severity of renal cystic phenotypes.

Main Methods:

  • Utilized two Pkd1-mutant mouse models representing different stages of PKD.
  • Administered sirolimus at a conventional low dose (3 ng/ml) and a higher dose (30-60 ng/ml).
  • Measured mTOR signaling activity (p-S6Rp Ser240/244) in renal tissues and evaluated cystogenesis, regression, fibrosis, and immune cell infiltration.

Main Results:

  • High-dose sirolimus, initiated during early disease stages, significantly reduced mTOR signaling, inhibited cyst formation, promoted cyst regression, and decreased fibrosis and immune cell infiltration.
  • Late-stage initiation of high-dose sirolimus did not yield significant benefits.
  • Low-dose sirolimus treatment did not substantially impact renal cystic disease progression.
  • Renal mTOR activity levels varied, with higher activity correlating with more severe PKD phenotypes.

Conclusions:

  • Conventional doses of sirolimus are insufficient to effectively inhibit mTOR activity in renal cystic tissues for PKD treatment.
  • Higher doses of mTOR inhibitors, particularly when administered early in the disease, demonstrate therapeutic potential in preclinical PKD models.
  • Strategies to enhance mTOR inhibitor bioavailability or kidney-specific targeting are crucial for improving therapeutic outcomes in PKD.

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