Shillingford JM et al. (2006) The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA 103: 5466–5471

Research published in the Proceedings of the National Academy of Sciences indicates that rapamycin—a drug already used as an immunosuppressant in renal transplantation—might be a potential treatment for the 12 million autosomal dominant polycystic kidney disease (ADPKD) sufferers worldwide. More than 85% of ADPKD cases are secondary to mutations in the PKD1 gene, which encodes polycystin-1.

In the present study, data from canine kidney cell clones showed that the cytoplasmic tail of polycystin-1 interacted with the kinase mTOR and with tuberin, a regulator of mTOR activity. The mTOR pathway in the cyst-lining epithelial cells was upregulated in mouse models with inactivated polycystin-1, and in human patients with ADPKD.

In PKD mouse models, treatment with rapamycin—an inhibitor of mTOR activity—induced apoptosis of cystic epithelial cells, reduced kidney weight by up to 76%, decreased cyst size and improved renal function. These effects were observed even when the PKD was secondary to mutations in genes unrelated to polycystin-1, indicating that activation of the mTOR pathway is the common mechanism underlying all renal cyst phenotypes.

Rapamycin was used as an immunosuppressant in four of seven ADPKD renal transplant recipients who retained one or both of their polycystic kidneys. Compared with those who did not receive rapamycin, there was a significantly greater reduction in polycystic kidney volume in the rapamycin-treated group (−8.6% vs −24.8%; P = 0.03).