Prostaglandin E2 promotes cell survival of glomerular epithelial cells via the EP4 receptor.
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.
Aoudjit
Lamine
L
McGill University Health Centre, Montreal, Quebec, Canada.
Potapov
Anna
A
Takano
Tomoko
T
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
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