Protective Effect of Prostaglandin EP4-Receptor Agonist on Anti-glomerular Basement Membrane Antibody-Associated Nephritis

Prostaglandin E2-receptor subtypes, EP1, EP2, EP3, and EP4, are present in the kidney. The aim of this study was to elucidate the anti-nephritic effect of an EP4-receptor agonist on an experimental nephritic model. Mice were injected i.v. with anti-glomerulus antiserum to induce nephritis. Nephritic glomeruli generated more prostaglandin E2 (2.6 and 0.7 ng) and less cyclic AMP than normal glomeruli (11 and 26 pmol). The production of cyclic AMP in nephritic glomeruli increased 67% in response to AE1-329, an EP4 agonist, at 10−5. Nephritic glomeruli expressed a lesser amount of mRNA of prostaglandin E2-receptor subtypes as compared with normal glomeruli. AE1-329 was administered s.c. at 100 µg/kg per day for 3 weeks. AE1-329 suppressed the increase in creatinine and cholesterol compared to those in the control nephritic mice. AE1-329-treated nephritic mice had less crescentic glomeruli and less deposition of rabbit IgG (anti-glomerular basement membrane antibody) in glomeruli than the control mice. AE1-329 prevented the development of glomerulonephritis. These findings suggest that EP4-receptor agonists are a promising drug to prevent the development of glomerulonephritis.