What Drives Cyst Formation in PKD?

Abstract

Polycystic kidney disease (PKD) is the most common genetic cause of chronic kidney disease, with an incidence of 1:400 to 1:1000.1 PKD is characterized by many large fluid-filled cysts in the kidney and often leads to end-stage renal failure. Intensive work from numerous international teams has succeeded in identifying three genes that account for almost all cases of PKD: polycystin-1 ( PC-1 ), polycystin-2 ( PC-2 ), and polycystic kidney and hepatic disease 1 ( Pkhd1 ).2–4 Autosomal dominant PKD is caused by mutations in PC-1 or PC-2. PC-1 encodes a protein with a large extracellular domain, 11 transmembrane domains, and a cytoplasmic tail . PC-2 encodes a transient receptor potential channel with six transmembrane domains that resembles PC-1. Autosomal recessive PKD is caused by mutations in Pkhd1, another protein with a large extracellular domain, a single transmembrane domain, and a cytoplasmic domain. Although the loci responsible for PKD are known, it is still poorly understood why mutations in PC-1 , PC-2 , and Pkhd1 result in cyst formation. Numerous models have been proposed to account for the development of cysts.1 Recent notions, which raise a great deal of interest, are that ciliary function and/or planar cell polarity (PCP) is disrupted during cyst formation. The primary cilium is an antenna-like structure that emerges from the apical surface of kidney epithelial cells, which has been found to be a key signaling center for many developmental pathways.5 A role for …