Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells

Qi Qian, Larry W. Hunter, Ming Li, Miquel Marin-Padilla, Y. S. Prakash, Stefan Somlo, Peter C. Harris, Vicente E. Torres, Gary C. Sieck

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


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 Pkd2WS25 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+], 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.

Original languageEnglish (US)
Pages (from-to)1875-1880
Number of pages6
JournalHuman molecular genetics
Issue number15
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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