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

TLDR

Autosomal‑dominant polycystic kidney disease is a common genetic disorder that often progresses to renal failure and is mainly caused by mutations in polycystin‑1, whose function remains poorly understood and for which no preventive therapy exists. We found that the PC1 cytoplasmic tail binds tuberin, causing aberrant mTOR activation in cyst‑lining cells, and that rapamycin treatment markedly reduces cystogenesis in mouse models and kidney size in human patients, demonstrating that mTOR inhibition is a viable therapy for ADPKD.

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.