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††, and
- Thomas Weimbs*,‡‡
- *Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610;
- §Department of Cell Biology, Lerner Research Institute, and
- ¶Glickman Urological Institute, The Cleveland Clinic, Cleveland, OH 44195; Departments of
- ‡Pediatrics,
- ‖Radiology, and Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106;
- **Division of Nephrology, Department of Medicine, University Hospital Freiburg, 79106 Freiburg, Germany; and
- ††Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Edited by John A. Carbon, University of California, Santa Barbara, CA, and approved February 8, 2006
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↵ †J.M.S. and N.S.M. contributed equally to this work. (received for review November 7, 2005)
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.
Footnotes
- ‡‡To whom correspondence should be addressed. E-mail: weimbs{at}lifesci.ucsb.edu
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See Commentary on page 5247.
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Author contributions: J.M.S., N.S.M., S.H.L., R.H., C.A.F., A.C.N., D.A.G., A.K.-Z., G.W., and T.W. designed research; J.M.S., N.S.M., C.H.L., S.H.L., R.H., N.B., C.A.F., and A.K.-Z. performed research; K.B.P. and G.G.G. contributed new reagents/analytic tools; J.M.S., N.S.M., C.H.L., S.H.L., R.H., C.A.F., and T.W. analyzed data; and J.M.S. and T.W. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- ADPKD,
- autosomal-dominant polycystic kidney disease;
- DOX,
- doxycycline;
- H&E,
- hematoxylin and eosin;
- MDCK,
- Madin–Darby canine kidney.
Abbreviations:
- © 2006 by The National Academy of Sciences of the USA
