EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells.
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.
Elberg
Gerard
G
Department of Pediatrics, The University of Oklahoma Health Sciences Center, 940 N. E. 13th St., 2B2309, Oklahoma City, OK 73104, USA. gerard-elberg@ouhsc.edu
Elberg
Dorit
D
Lewis
Teresa V
TV
Guruswamy
Suresh
S
Chen
Lijuan
L
Logan
Charlotte J
CJ
Chan
Michael D
MD
Turman
Martin A
MA
D017209:Apoptosis; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014162:Transfection
C545644:PTGER2 protein, human; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP; D015232:Dinoprostone