Abstract
Mutations in the polycystin genes, PKD1 or PKD2, results in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Although a genetic basis of ADPKD is established, we lack a clear understanding of polycystin proteins' functions as ion channels. This question remains unsolved largely because polycystins localize to the primary cilium - a tiny, antenna-like organelle. Using a new ADPKD mouse model, we observe primary cilia that are abnormally long in cells associated with cysts after conditional ablation of Pkd1 or Pkd2. Using primary cultures of collecting duct cells, we show that polycystin-2, but not polycystin-1, is a required subunit for the ion channel in the primary cilium. The polycystin-2 channel preferentially conducts K+ and Na+; intraciliary Ca2+, enhances its open probability. We introduce a novel method for measuring heterologous polycystin-2 channels in cilia, which will have utility in characterizing PKD2 variants that cause ADPKD.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is an adult-onset disease characterized by focal cyst development resulting from heterozygous mutations in PKD1 or PKD2 (Brasier and Henske, 1997; Grantham, 2001; Hughes et al, 1995; Mochizuki et al, 1996)
Previous work demonstrated that the human ADPKD kidney cyst phenotype can be reproduced in mice 14 weeks after conditional ablation of nephron-localized Pkd1 or Pkd2 (Ma et al, 2013)
Immunoblots were performed from pIMCD cell lysates from 2 week and 2 month doxycyclineablated Arl13b-EGFPtg:cre; Pkd2fl/fl (cPkd2) or 2 week post-treatment of Arl13b-EGFPtg:cPkd1 mice, indicating that the recombinase substantially reduced polycystin-2 or polycystin-1 protein expression (Figure 1B)
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is an adult-onset disease characterized by focal cyst development resulting from heterozygous mutations in PKD1 or PKD2 (Brasier and Henske, 1997; Grantham, 2001; Hughes et al, 1995; Mochizuki et al, 1996). The onset of kidney cyst development in adult mice following conditional inactivation of Pkd or the intraflagellar transport protein kinesin, KIF3a (required for cilia formation), progresses well into adulthood, in analogy to the late progression of ADPKD in humans (Davenport et al, 2007; Piontek et al, 2007; Shibazaki et al, 2008).
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