Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic human disease. About 85% of ADPKD cases are caused by mutations in the PKD1 gene, whereas the remaining cases are caused by defects in the PKD2 gene. The PKD1 protein, polycystin-1 (PC1), is a large integral protein whose function is not clear. PC2, the PKD2 protein, is a membrane protein believed to function as a Ca2+ permeable cation channel in the endoplasmic reticulum and plasma membrane. Recent findings suggest that the PC1/PC2 complex may function as a mechanoreceptor in primary cilia of mouse embryonic renal epithelia and, more speculatively may contribute to flow-regulated epithelial morphogenesis. We will study the function of PC1/PC2 in primary cultures of normal human proximal renal epithelial cells, and of ADPKD cyst cells with the following Specific Aims: 1. Complete the characterization of flow-induced Ca 2+ signaling and 28 pS cation channel activity in normal human renal epithelial cells and ADPKD cells, and test the hypothesis that they are related. 2.Test effect of modulation of PC2 expression in human kidney cells on flow-induced Ca2+ signaling and on 28 pS cation channel activity. 3:Compare effects of expression of CD16.7-PKD1 (115-226) and full-length polycystin 1 on flow-induced Ca2+ signaling and 28 pS cation channel activity.
| Xu, Chang; Shmukler, Boris E; Nishimura, Katherine et al. (2009) Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. Am J Physiol Renal Physiol 296:F1464-76 |
| Xu, Chang; Rossetti, Sandro; Jiang, Lianwei et al. (2007) Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling. Am J Physiol Renal Physiol 292:F930-45 |
| Malek, Adel M; Xu, Chang; Kim, Edward S et al. (2007) Hypertonicity triggers RhoA-dependent assembly of myosin-containing striated polygonal actin networks in endothelial cells. Am J Physiol Cell Physiol 292:C1645-59 |
