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


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.

SUBMITTER: Shillingford JM 

PROVIDER: S-EPMC1459378 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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

Shillingford Jonathan M JM   Murcia Noel S NS   Larson Claire H CH   Low Seng Hui SH   Hedgepeth Ryan R   Brown Nicole N   Flask Chris A CA   Novick Andrew C AC   Goldfarb David A DA   Kramer-Zucker Albrecht A   Walz Gerd G   Piontek Klaus B KB   Germino Gregory G GG   Weimbs Thomas T  

Proceedings of the National Academy of Sciences of the United States of America 20060327 14


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,  ...[more]

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