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Published on: June 23, 2015
Everolimus retards cyst growth and preserves kidney function in a rodent model for polycystic kidney disease
Ming Wu1, Patricia R Wahl, Michel Le Hir
1Physiological Institute , University Zürich Irchel, Zürich, Switzerland.
Background/Aims:
Rapamycin inhibits cyst growth in polycystic kidney disease by targeting the mammalian target of rapamycin (mTOR). To determine if this is a class effect of the mTOR inhibitors, we examined the effect of everolimus, the analogue of rapamycin, on disease progression in the Han:SPRD rat model of polycystic kidney disease.
Methods:
Four-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) Han:SPRD rats were administered everolimus or vehicle (3 mg/kg/day) by gavage for 5 weeks. Kidney function and whole-blood trough levels of everolimus were monitored. After treatment kidney weight and cyst volume density were assessed. Tubule epithelial cell proliferation was assessed by BrdU staining.
Results:
Everolimus trough levels between 5 and 7 microg/l were sufficient to significantly reduce kidney and cyst volume density by approximately 50 and 40%, respectively. The steady decrease of kidney function in Cy/+ rats was reduced by 30% compared with vehicle-treated Cy/+ rats. Everolimus treatment markedly reduced the number of 5-bromo-2-deoxyuridine-labeled nuclei in cyst epithelia. Body weight gain and kidney function were impaired in everolimus-treated wild-type rats.
Conclusion:
Moderate dosage of everolimus inhibits cystogenesis in Han:SPRD rats. The inhibitory effect of everolimus appears to represent a class effect of mTOR inhibitors.
Insights
Everolimus, an mTOR inhibitor, significantly reduced cyst growth and improved kidney function in a rat model of polycystic kidney disease. This suggests mTOR inhibitors may be a viable treatment class for this condition.
Area of Science:
- Nephrology
- Pharmacology
- Genetics
Background:
- Polycystic kidney disease (PKD) is characterized by progressive cyst development.
- Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has shown efficacy in reducing cyst growth in PKD.
- It remains to be determined if this effect is specific to rapamycin or a class effect of mTOR inhibitors.
Purpose of the Study:
- To investigate the efficacy of everolimus, an mTOR inhibitor analogue of rapamycin, in treating polycystic kidney disease.
- To assess the impact of everolimus on cystogenesis and kidney function in the Han:SPRD rat model of PKD.
Main Methods:
- Male Han:SPRD rats (heterozygous cystic Cy/+ and wild-type +/+) were treated with everolimus (3 mg/kg/day) or vehicle for 5 weeks.
- Kidney function, everolimus blood levels, kidney weight, cyst volume density, and tubule epithelial cell proliferation (BrdU staining) were assessed.
Main Results:
- Everolimus significantly reduced kidney and cyst volume by approximately 50% and 40%, respectively.
- Kidney function decline was reduced by 30% in everolimus-treated Cy/+ rats compared to controls.
- Cell proliferation in cyst epithelia was markedly reduced by everolimus treatment, though wild-type rats showed impaired kidney function and weight gain.
Conclusions:
- Everolimus demonstrates significant inhibitory effects on cystogenesis in the Han:SPRD rat model of PKD.
- These findings support the hypothesis that mTOR inhibitors represent a class effect for treating polycystic kidney disease.
