Prostaglandin E2promotes cell survival of glomerular epithelial cells via the EP4 receptor

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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) E2in 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 PGE2generation, increased activation of extracellular signal-regulated kinase, decreased apoptosis, and increased cell proliferation. Rat GEC abundantly expressed the EP4 isoform of PGE2receptor. Induction of COX-2 and addition of exogenous PGE2both 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. PGE2also 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 PGE2may have anti-apoptotic/protective effect on GEC via the EP4 receptor of PGE2.