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

Wahl, Patricia R. and Serra, Andreas L. and Le Hir, Michel and Molle, Klaus D. and Hall, Michael N. and Wüthrich, Rudolf P.. (2006) Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrology, Dialysis, Transplantation, 21 (3). pp. 598-604.

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Official URL: http://edoc.unibas.ch/dok/A5262070

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Abstract

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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Oxford University Press
ISSN:0931-0509
e-ISSN:1460-2385
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:09 Nov 2017 08:12
Deposited On:22 Mar 2012 13:23

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