Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease

Abstract

One of the most important abnormalities of the tubular epithelial cells lining the cysts as well as noncystic tubular epithelium is a disturbance in the balance between tubular cell proliferation and apoptosis. Activation of the mammalian target of rapamycin signaling pathway results in increased cell proliferation. Recent studies suggested abnormalities of the mammalian target of rapamycin signaling pathway in polycystic kidney disease. Mammalian target of rapamycin inhibition with sirolimus or everolimus results in attenuation of cyst formation in rat and mouse models of polycystic kidney disease. Apoptosis is a pathologic feature of most models of polycystic kidney disease, including human polycystic kidneys. Caspases, the major mediators of apoptosis, are increased in polycystic kidney disease kidneys. Both in vitro and in vivo studies suggest that caspase or apoptosis inhibition attenuates cyst formation. This review focuses on mammalian target of rapamycin and apoptosis signaling pathways in polycystic kidney disease and the role of mammalian target of rapamycin inhibitors and apoptosis inhibitors as potential therapies to reduce cyst formation.