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NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(3):598-604; doi:10.1093/ndt/gfi181
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Experimental Nephrology

Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)

Patricia R. Wahl1, Andreas L. Serra1,2, Michel Le Hir3, Klaus D. Molle4, Michael N. Hall4 and Rudolf P. Wüthrich1,2

1 Physiological Institute, 3 Anatomical Institute, University Zürich-Irchel, 2 Division of Nephrology, University Hospital, Zürich and 4 Division of Biochemistry, Biozentrum, University of Basel, Switzerland

Correspondence and offprint requests to: Prof. Dr Rudolf P. Wüthrich, Renal Division, University Hospital, Rämistrasse 100, 8091 Zürich, Switzerland. Email: rudolf.wuethrich{at}usz.ch

Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the effect of the mTOR inhibitor sirolimus (rapamycin) on renal functional loss and cyst progression in the Han:SPRD rat model of ADPKD.

Methods. Five-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) rats were administered sirolimus (2 mg/kg/day) orally through the drinking water for 3 months. The renal function was monitored throughout the treatment phase, and rats were sacrificed thereafter. Kidneys were analysed histomorphometrically, and for the expression and phosphorylation of S6K, a well-characterized target of mTOR in the regulation of cell growth.

Results. The steady increase in BUN and creatinine in Cy/+ rats was reduced by 39 and 34%, respectively with sirolimus after 3 months treatment. Kidney weight and 2-kidney/total body weight (2K/TBW) ratios were reduced by 34 and 26% in sirolimus-treated Cy/+ rats. Cyst volume density was also reduced by 18%. Of importance, Cy/+ rats displayed enhanced levels of total and phosphorylated S6K. Sirolimus effectively reduced total and phosphorylated levels of S6K.

Conclusion. We conclude that oral sirolimus markedly delays the loss of renal function and retards cyst development in Han:SPRD rats with ADPKD. Our data also suggest that activation of the S6K signalling pathway plays an important role in the pathogenesis of PKD. Sirolimus could be a useful drug to retard progressive renal failure in patients with ADPKD.

Keywords: ADPKD; Han:SPRD rats; mTOR; rapamycin; sirolimus; S6K


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