Polycystic kidney disease: a case of suppressed autophagy?
Autosomal-dominant polycystic kidney disease is the most common form of polycystic kidney disease in adults and is caused by a mutation in the polycystic kidney disease 1 or 2 genes, which encode, respectively, polycystin-1 and polycystin-2. Autophagy is present in polycystic kidneys in rat and mouse models of polycystic kidney disease. Autophagy has yet to be shown in human polycystic kidney disease kidneys. The mechanism of cyst growth has been studied extensively in vitro and in vivo. Multiple molecules and signaling pathways have been implicated in cyst growth including mammalian target of rapamycin, the renin-angiotensin-aldosterone system, vasopressin and cyclic adenosine monophosphate, epidermal growth factor and insulin-like growth factor tyrosine kinases, vascular endothelial growth factor, extracellular signal-related kinase, tumor necrosis factor-α, cyclin-dependent kinases, caspases and apoptosis, and cyclic adenosine monophosphate-activated protein kinases. Many of the agents that inhibit these signaling pathways and slow cyst growth are also autophagy inducers such as mammalian target of rapamycin inhibitors, cyclin-dependent kinase inhibitors, caspase inhibitors, tyrosine kinase inhibitors, metformin, curcumin, and triptolide. There are reasons to believe that suppression of autophagy may play a role in cyst formation and growth. This review presents the hypothesis that suppression of autophagy may play a role in cyst formation and growth, based on the following: (1) many of the agents that protect against polycystic kidney disease also induce autophagy, (2) suppression of autophagy in polycystic kidney disease 1 knockout cells, (3) a defect in autophagy in congenital polycystic kidney mice with polycystic kidney disease, (4) how suppressed autophagy may relate to apoptosis in polycystic kidney disease, and (5) conditions with defective cilia, the ciliopathies, are associated with decreased autophagy.
Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO.
Kameswaran
K
Ravichandran
Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO. Electronic address: charles.edelstein@ucdenver.edu.
Charles L
CL
Edelstein
D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D002923:Cilia / Q000502:physiology; D006801:Humans; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000209:etiology / Q000473:pathology*; D011506:Proteins / Q000502:physiology; D015398:Signal Transduction
C115130:OFD1 protein, human; D011506:Proteins
Polycystic kidney; apoptosis; autophagy