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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1622    most recent 00036.2007v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Elberg, G. Articles by Turman, M. A. Search for Related Content PubMed PubMed Citation Articles by Elberg, G. Articles by Turman, M. A.

EP₂ receptor mediates PGE₂-induced cystogenesis of human renal epithelial cells

¹Department of Pediatrics and ²College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Submitted 19 January 2007 ; accepted in final form 28 August 2007

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by formation of cysts from tubular epithelial cells. Previous studies indicate that secretion of prostaglandin E₂ (PGE₂) into cyst fluid and production of cAMP underlie cyst expansion. However, the mechanism by which PGE₂ directly stimulates cAMP formation and modulates cystogenesis is still unclear, because the particular E-prostanoid (EP) receptor mediating the PGE₂ effect has not been characterized. Our goal is to define the PGE₂ receptor subtype involved in ADPKD. We used a three-dimensional cell-culture system of human epithelial cells from normal and ADPKD kidneys in primary cultures to demonstrate that PGE₂ induces cyst formation. Biochemical evidence gathered by using real-time RT-PCR mRNA analysis and immunodetection indicate the presence of EP₂ receptor in cystic epithelial cells in ADPKD kidney. Pharmacological evidence obtained by using PGE₂-selective analogs further demonstrates that EP₂ mediates cAMP formation and cystogenesis. Functional evidence for a role of EP₂ receptor in mediating cAMP signaling was also provided by inhibiting EP₂ receptor expression with transfection of small interfering RNA in cystic epithelial cells. Our results indicate that PGE₂ produced in cyst fluid binds to adjacent EP₂ receptors located on the apical side of cysts and stimulates EP₂ receptor expression. PGE₂ binding to EP₂ receptor leads to cAMP signaling and cystogenesis by a mechanism that involves protection of cystic epithelial cells from apoptosis. The role of EP₂ receptor in mediating the PGE₂ effect on stimulating cyst formation may have direct pharmacological implications for the treatment of polycystic kidney disease.

prostaglandin; E-prostanoid; butaprost; G-protein coupled receptor; polycystic kidney disease, three-dimensional cell culture system