PMID:12874107

Citation	Qian, Q, Hunter, LW, Li, M, Marin-Padilla, M, Prakash, YS, Somlo, S, Harris, PC, Torres, VE and Sieck, GC (2003) Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum. Mol. Genet. 12:1875-80
Abstract	Autosomal-dominant polycystic kidney disease is a multiorgan disease and its vascular manifestations are common and life-threatening. Despite this, little is known about their pathogenesis. Somatic mutations to the normal PKD allele in cystic epithelia and cyst development associated with the unstable Pkd2(WS25) allele suggest a two-hit model of cystogenesis. However, it is unclear if this model can account for the cardiovascular pathology or if haploinsufficiency alone is disease-associated. In the present study, we found a decreased polycystin-2 (PC2, protein encoded by Pkd2 gene) expression in Pkd2( +/-) vessels, roughly half the wild-type level, and an enhanced level of intracranial vascular abnormalities in Pkd2 (+/-) mice when induced to develop hypertension. Consistent with these observations, freshly dissociated Pkd2 (+/-) vascular smooth muscle cells have significantly altered intracellular Ca(2+) homeostasis. The resting [Ca(2+)](i) is 17.1% lower in Pkd2 (+/-) compared with wild-type cells (P=0.0003) and the total sarcoplasmic reticulum Ca(2+) store (emptied by caffeine plus thapsigargin) is decreased (P<0.0001). The store operated Ca(2+) (SOC) channel activity is also decreased in Pkd2 (+/-) cells (P=0.008). These results indicate that inactivation of just one Pkd2 allele is sufficient to significantly alter intracellular Ca(2+) homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca(2+) store in VSMCs. Based on these findings, and the fact that [Ca(2+)](i) signaling is essential to the regulation of contraction, production and secretion of extracellular matrix, cellular proliferation and apoptosis, we propose that the abnormal intracellular Ca(2+) regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype.
Links	PubMed
Keywords	Alleles; Animals; Blotting, Western; Calcium/metabolism; Calcium Signaling; DNA Primers; Disease Models, Animal; Fluorescent Antibody Technique; Membrane Proteins/deficiency; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mice, Mutant Strains; Muscle, Smooth, Vascular/metabolism; Polycystic Kidney, Autosomal Dominant/genetics; Polymerase Chain Reaction; TRPP Cation Channels
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