Prostaglandin E2 promotes cell survival of glomerular epithelial cells via the EP4 receptor

Am J Physiol Renal Physiol. 2006 Jun;290(6):F1534-42. doi: 10.1152/ajprenal.00267.2005. Epub 2006 Jan 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 3
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology*
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Enzyme Induction
  • Epithelial Cells / cytology
  • Gene Expression
  • Kidney Glomerulus / cytology*
  • Nephrosis / chemically induced
  • Phosphoric Diester Hydrolases / pharmacology
  • Phosphoric Diester Hydrolases / physiology*
  • Proteinuria
  • Puromycin Aminonucleoside / pharmacology
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / physiology*
  • Receptors, Prostaglandin E, EP4 Subtype
  • Thiophenes / pharmacology
  • Transfection
  • Triazoles / pharmacology

Substances

  • L-161982
  • Ptger4 protein, rat
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype
  • Thiophenes
  • Triazoles
  • Puromycin Aminonucleoside
  • Cyclooxygenase 2
  • Phosphoric Diester Hydrolases
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Pde2a protein, rat
  • Casp3 protein, rat
  • Caspase 3
  • Caspases