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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 296/6/F1464    most recent 90542.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Google Scholar Articles by Xu, C. Articles by Alper, S. L. PubMed PubMed Citation Articles by Xu, C. Articles by Alper, S. L.

Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Ca_i²⁺ signaling in human ADPKD cyst epithelial cells

¹Molecular and Vascular Medicine and Renal Divisions, Beth Israel Deaconess Medical Center and Departments of ²Medicine and ³Surgery, Harvard Medical School, Boston, Massachusetts; ⁴Departments of Medicine and Biochemistry, Mayo Medical School, Rochester, Minnesota; ⁵Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico; and ⁶Department of Medicine, University of Indiana School of Medicine, Indianapolis, Indiana

Submitted 11 September 2008 ; accepted in final form 24 February 2009

Flow-induced cytosolic Ca²⁺ Ca_i²⁺ signaling in renal tubular epithelial cells is mediated in part through P2 receptor (P2R) activation by locally released ATP. The ability of P2R to regulate salt and water reabsorption has suggested a possible contribution of ATP release and paracrine P2R activation to cystogenesis and/or enlargement in autosomal dominant polycystic kidney disease (ADPKD). We and others have demonstrated in human ADPKD cyst cells the absence of flow-induced Ca_i²⁺ signaling exhibited by normal renal epithelial cells. We now extend these findings to primary and telomerase-immortalized normal and ADPKD epithelial cells of different genotype and of both proximal and distal origins. Flow-induced elevation of Ca_i²⁺ concentration ([Ca²⁺]_i) was absent from ADPKD cyst cells, but in normal cells was mediated by flow-sensitive ATP release and paracrine P2R activation, modulated by ecto-nucleotidase activity, and abrogated by P2R inhibition or extracellular ATP hydrolysis. In contrast to the elevated ATP release from ADPKD cells in static isotonic conditions or in hypotonic conditions, flow-induced ATP release from cyst cells was lower than from normal cells. Extracellular ATP rapidly reduced thapsigargin-elevated [Ca²⁺]_i in both ADPKD cyst and normal cells, but cyst cells lacked the subsequent, slow, oxidized ATP-sensitive [Ca²⁺]_i recovery present in normal cells. Telomerase-immortalized cyst cells also exhibited altered CD39 and P2X7 mRNA levels. Thus the loss of flow-induced, P2R-mediated Ca_i²⁺ signaling in human ADPKD cyst epithelial cells was accompanied by reduced flow-sensitive ATP release, altered purinergic regulation of store-operated Ca²⁺ entry, and altered expression of gene products controlling extracellular nucleotide signaling.

autosomal dominant polycystic kidney disease; telomerase; monocilium; shear stress; luciferase; fura 2

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