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Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5466-71. Epub 2006 Mar 27.

The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

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1
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610, USA.

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.

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PMID:
16567633
PMCID:
PMC1459378
DOI:
10.1073/pnas.0509694103
[Indexed for MEDLINE]
Free PMC Article
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