title: Prostaglandin E2 promotes cell survival of glomerular epithelial cells via the EP4 receptor.
abstract: Visceral glomerular epithelial cells (GEC) are crucial for glomerular permselectivity and structural integrity in the kidney. The current study addressed the role of cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 in GEC survival. We generated a subclone of cultured rat GEC, which overexpress COX-2 in an inducible manner. When COX-2 was induced, GEC survived better in serum-deprived conditions. Induction of COX-2 was correlated with increased PGE2 generation, increased activation of extracellular signal-regulated kinase, decreased apoptosis, and increased cell proliferation. Rat GEC abundantly expressed the EP4 isoform of PGE2 receptor. Induction of COX-2 and addition of exogenous PGE2 both lead to decreased serum deprivation-induced apoptosis, which was accompanied by activation of the survival kinase Akt. Anti-apoptotic effect of COX-2 induction was reversed by the specific inhibitor of the EP4 receptor, L-161982. PGE2 also inhibited puromycin aminonucleoside-induced GEC apoptosis in vitro. Acute puromycin aminonucleoside nephrosis (PAN) is a rat model of GEC injury and proteinuria. In rats with PAN, glomerular apoptosis, quantified as caspase-3 activity, as well as urinary protein excretion were significantly increased, compared with control rats. Administration of L-161982 in rats with PAN further exacerbated caspase-3 activation and proteinuria. Thus COX-2 and its product PGE2 may have anti-apoptotic/protective effect on GEC via the EP4 receptor of PGE2.
authors.affiliation: McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Lamine
authors.initials: L
authors.lastname: Aoudjit
authors.forename: Anna
authors.initials: A
authors.lastname: Potapov
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000166:cytology; D015870:Gene Expression; D007678:Kidney Glomerulus / Q000166:cytology*; D009401:Nephrosis / Q000139:chemically induced; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology / Q000502:physiology*; D011507:Proteinuria; D011692:Puromycin Aminonucleoside / Q000494:pharmacology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes / Q000494:pharmacology; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology
chemical_list: C508711:L-161982; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; D014230:Triazoles; D011692:Puromycin Aminonucleoside; D051546:Cyclooxygenase 2; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517278:Pde2a protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases