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

Jonathan M. Shillingford, Noel S. Murcia, Claire H. Larson, Seng Hui Low, Ryan Hedgepeth, Nicole Brown, Chris A. Flask, Andrew C. Novick, David A. Goldfarb, Albrecht Kramer-Zucker, Gerd Walz, Klaus B. Piontek, Gregory G. Germino, Thomas Weimbs

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5466-5471
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number14
DOIs
StatePublished - Apr 4 2006

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Keywords

  • Rapamycin
  • Renal epithelial cells
  • Tuberin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Shillingford, J. M., Murcia, N. S., Larson, C. H., Low, S. H., Hedgepeth, R., Brown, N., Flask, C. A., Novick, A. C., Goldfarb, D. A., Kramer-Zucker, A., Walz, G., Piontek, K. B., Germino, G. G., & Weimbs, T. (2006). The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proceedings of the National Academy of Sciences of the United States of America, 103(14), 5466-5471. https://doi.org/10.1073/pnas.0509694103