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

Gerard Elberg, Dorit Elberg, Teresa V. Lewis, Suresh Guruswamy, Lijuan Chen, Charlotte J. Logan, Michael D. Chan, Martin A. Turman
2007 AJP - Renal Physiology  
polycystic kidney disease (ADPKD) is characterized by formation of cysts from tubular epithelial cells. Previous studies indicate that secretion of prostaglandin E 2 (PGE2) into cyst fluid and production of cAMP underlie cyst expansion. However, the mechanism by which PGE 2 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 PGE 2 receptor
more » ... 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 PGE 2 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 EP 2 receptor in mediating cAMP signaling was also provided by inhibiting EP 2 receptor expression with transfection of small interfering RNA in cystic epithelial cells. Our results indicate that PGE 2 produced in cyst fluid binds to adjacent EP 2 receptors located on the apical side of cysts and stimulates EP 2 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.
doi:10.1152/ajprenal.00036.2007 pmid:17728378 fatcat:2qrb73xu2vfc7ob75yetk2qi4q