Advances in the pathogenesis and treatment of polycystic kidney disease.
OBJECTIVE
Polycystic kidney disease (PKD) is the most common genetic cause of chronic renal failure. Mouse models of PKD, especially those with mutations in genes that are orthologous to human disease genes, have provided insights into the pathogenesis of cyst formation and advanced the preclinical testing of new drugs.


RESULTS
PKD is a ciliopathy that arises from abnormalities in the primary cilium, a sensory organelle present on the surface of most cells. The primary cilium is required for the maintenance of planar cell polarity, which regulates tubular diameter. Acute kidney injury stimulates cell proliferation and promotes cyst formation in a mouse model of PKD. Studies of signaling pathways that are perturbed in PKD have identified new potential therapeutic targets. Drugs that have shown beneficial effects in orthologous animal models of PKD include tolvaptan, octreotide, src inhibitors, CFTR inhibitors, pioglitazone, etanercept, and triptolide.


CONCLUSIONS
Abnormalities in the primary cilium perturb signaling pathways that regulate renal epithelial cell growth and differentiation and lead to the formation of kidney cysts. Acute kidney injury promotes cyst formation and may underlie the variability in disease progression that is observed in affected individuals. Several promising new therapeutic agents that have been validated in orthologous animal models have entered clinical trials in humans.
Patel
Vishal
V
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chowdhury
Renuka
R
Igarashi
Peter
P
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D016764:Cell Polarity; D002923:Cilia / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000502:physiology; D015282:Octreotide / Q000627:therapeutic use; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000209:etiology*; D011687:Purines / Q000627:therapeutic use; D000077546:Roscovitine; D020123:Sirolimus / Q000627:therapeutic use; D050396:TRPP Cation Channels / Q000502:physiology
D065092:Antidiuretic Hormone Receptor Antagonists; D016547:Kinesins; D015282:Octreotide; D011687:Purines; D000077546:Roscovitine; D020123:Sirolimus; D050396:TRPP Cation Channels; C087415:KIF3A protein, human