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Published ahead of print on January 14, 2010
J Am Soc Nephrol 21: 489-497, 2010
© 2010 American Society of Nephrology
doi: 10.1681/ASN.2009040421
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BASIC RESEARCH

Rapamycin Ameliorates PKD Resulting from Conditional Inactivation of Pkd1

Jonathan M. Shillingford*,{dagger}, Klaus B. Piontek{ddagger}, Gregory G. Germino{ddagger} and Thomas Weimbs*,{dagger}

*Department of Molecular, Cellular, and Developmental Biology and
{dagger}Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California; and
{ddagger}Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Correspondence: Dr. Thomas Weimbs, Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106-9610. Phone: 805-893-4144; Fax: 805-893-4724; E-mail: weimbs{at}lifesci.ucsb.edu

Received for publication November 18, 2009. Aberrant activation of the mammalian target of rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective in several rodent models of PKD, but these models result from mutations in genes other than Pkd1 and Pkd2, which are the primary genes responsible for human autosomal dominant PKD. To address this limitation, we tested the efficacy of rapamycin in a mouse model that results from conditional inactivation of Pkd1. Mosaic deletion of Pkd1 resulted in PKD and replicated characteristic features of human PKD including aberrant mTOR activation, epithelial proliferation and apoptosis, and progressive fibrosis. Treatment with rapamycin was highly effective: It reduced cyst growth, preserved renal function, inhibited epithelial cell proliferation, increased apoptosis of cyst-lining cells, and inhibited fibrosis. These data provide in vivo evidence that rapamycin is effective in a human-orthologous mouse model of PKD.


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