Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease.
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.
Edelstein
Charles L
CL
Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Box C281, 4200 E. 9th Avenue, Denver, CO 80262, USA. Charles.edelstein@uchsc.edu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020169:Caspases