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

JM Shillingford, NS Murcia… - Proceedings of the …, 2006 - National Acad Sciences
JM Shillingford, NS Murcia, CH Larson, SH Low, R Hedgepeth, N Brown, CA Flask
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
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 …
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.
National Acad Sciences