The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.
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.
Shillingford
Jonathan M
JM
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610, USA.
Murcia
Noel S
NS
Larson
Claire H
CH
Low
Seng Hui
SH
Hedgepeth
Ryan
R
Brown
Nicole
N
Flask
Chris A
CA
Novick
Andrew C
AC
Goldfarb
David A
DA
Kramer-Zucker
Albrecht
A
Walz
Gerd
G
Piontek
Klaus B
KB
Germino
Gregory G
GG
Weimbs
Thomas
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000473:pathology*; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels
D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C546842:MTOR protein, human; C546843:mTOR protein, mouse