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*‡‡

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.

mTOR is out of control in polycystic kidney disease
Keith E. Mostov*