Journal
HUMAN MOLECULAR GENETICS
Volume 12, Issue 15, Pages 1875-1880Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddg190
Keywords
-
Funding
- NIDDK NIH HHS [DK 44863] Funding Source: Medline
- NIGMS NIH HHS [GM 56686] Funding Source: Medline
Ask authors/readers for more resources
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 Ca2+ homeostasis. The resting [Ca2+](i) is 17.1% lower in Pkd2 (+/-) compared with wild-type cells (P=0.0003) and the total sarcoplasmic reticulum Ca2+ store (emptied by caffeine plus thapsigargin) is decreased (P<0.0001). The store operated Ca2+ (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 Ca2+ homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca2+ store in VSMCs. Based on these findings, and the fact that [Ca2+](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 Ca2+ regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available