Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the USA resulting in chronic kidney disease and the need for dialysis and transplantation. Approximately 85% of cases of ADPKD are caused by a mutation in the Pkd1 gene that encodes polycystin-1, a large membrane receptor. The Pkd1 gene mutation results in abnormal proliferation in tubular epithelial cells, which plays a crucial role in cyst development and/or growth in PKD. Activation of the proliferative mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated in polycystic kidneys from rodents and humans. mTOR inhibition with sirolimus or everolimus decreases cysts in most animal models of PKD including Pkd1 and Pkd2 gene deficient orthologous models of human disease. On the basis of animal studies, human studies were undertaken. Two large randomized clinical trials published in the New England Journal of Medicine of everolimus or sirolimus in ADPKD patients were very unimpressive and associated with a high side-effect profile. Possible reasons for the unimpressive nature of the human studies include their short duration, the high drop-out rate, suboptimal dosing, lack of randomization of "fast" and "slow progressors" and the lack of correlation between kidney size and kidney function in ADPKD. The future of mTOR inhibition in ADPKD is discussed.

Keywords: Everolimus; Mammalian target of rapamycin; Polycystic kidney; Polycystic kidney disease; Sirolimus.

Figure 1

mTOR signaling. mTOR exists in association with two different complexes, mTORC1 and mTORC2. mTORC1 consists of mTOR and regulatory associated protein of mTOR (Raptor), while mTORC2 consists of mTOR and rapamycin-independent companion of mTOR (Rictor). In the mTORC1 pathway, PI3K converts PIP₂ into PIP₃, which localizes Akt to the membrane. The TSC1 (hamartin) and TSC2 (tuberin) complex is inactivated by Akt-dependent phosphorylation. Inactivation of TSC2 results in activation of mTOR via the GTPase, Rheb. mTOR phosphorylates both p70 S6 kinase (p70S6K) and 4E-BP1 via independent pathways that promote cell proliferation. The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) to destabilize the association between mTORC1 and raptor, preventing the downstream phosphorylation of p70S6K. In the mTORC2 pathway, there is downstream signaling to the AGC kinases Akt, PKCα, and SGK1. Phosphorylation of Akt at Serine 473 by mTORC2 primes Akt for further phosphorylation at Threonine 308.