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NDT Advance Access originally published online on March 25, 2009
Nephrology Dialysis Transplantation 2009 24(8):2349-2353; doi:10.1093/ndt/gfp129
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Long-term rapamycin therapy in the Han:SPRD rat model of polycystic kidney disease (PKD)

Iram Zafar, Franck A. Belibi, Zhibin He and Charles L. Edelstein

Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, CO, USA

Correspondence and offprint requests to: Charles L. Edelstein; E-mail: charles.edelstein{at}ucdenver.edu



  Abstract

Background. Short-term studies have demonstrated that rapamycin or everolimus treatment decreases cyst formation and improves renal function in animal models of polycystic kidney disease (PKD). Autosomal dominant polycystic kidney disease (ADPKD) patients would likely require life-long treatment with rapamycin.

Methods. Male Han:SPRD rats with PKD (Cy/+) were treated with rapamycin (0.2 mg/kg/day IP) or vehicle from 1 to 12 months of age. Mean trough levels of rapamycin (ng/mL) were 6.6 ± 0.1 at 8 weeks of age. Twelve-month-old littermates (+/+) were used as normal controls.

Results. Twelve-month-old male Cy/+ rats treated with the vehicle had a more than doubling of kidney volume, severe chronic renal failure, severe hypertension and increased heart weight compared to normal littermate controls (+/+). After rapamycin treatment, 12-month-old Cy/+ rats had markedly improved kidney volume, renal function, blood pressure and heart weight not statistically different from controls. Rapamycin reduced the cyst volume density (CVD) by 72%. Mammalian target of rapamycin (mTOR) activation in the heart, as evidenced by a marked increase in the phospho-S6 protein that was inhibited by rapamycin, was demonstrated in 12-month-old Cy/+ rats.

Conclusion. In conclusion, long-term rapamycin treatment in Cy/+ rats results in a normalization of kidney volume, renal function, blood pressure and heart weight. The novel finding that rapamycin decreases hypertension, heart enlargement and mTOR signalling in the heart in PKD rats is reported. The only side effect of rapamycin treatment was an 11% decrease in body weight.

Keywords: chronic kidney disease; heart; mTOR; polycystic kidney; rapamycin

Received for publication: 23. 9.08
Accepted in revised form: 3. 3.09


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