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Human Molecular Genetics, 2003, Vol. 12, No. 15 1875-1880
DOI: 10.1093/hmg/ddg190
© 2003 Oxford University Press

Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells

Qi Qian1,*, Larry W. Hunter2, Ming Li1, Miguel Marin-Padilla3, Y.S. Prakash2, Stefan Somlo4, Peter C. Harris1, Vicente E. Torres1 and Gary C. Sieck2

1Department of Medicine, Division of Nephrology, 2Department of Physiology and Biophysics and 3Department of Pathology, Mayo Clinic, Rochester, MN, USA and 4Department of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, CT, USA

Received March 14, 2003; Revised May 14, 2003; Accepted May 28, 2003

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+]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.

* To whom correspondence should be addressed at: Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 5072846793; Fax: +1 5072669315; Email: qian.qi{at}mayo.edu


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