Restoration of renal function by a novel prostaglandin EP4 receptor-derived peptide in models of acute renal failure

摘要: Acute renal failure (ARF) is a serious medical complication characterized by an abrupt and sustained decline in function. Despite significant advances supportive care, there currently no effective treatment to restore PGE2 lipid hormone mediator abundantly produced the kidney, where it acts locally regulate function; several studies suggest that modulating EP4 receptor activity could improve function following kidney injury. An optimized peptidomimetic ligand of receptor, THG213.29, was tested for its efficacy (glomerular filtration rate, plasma flow, urine output) histological changes model ARF induced either cisplatin or artery occlusion Sprague-Dawley rats. THG213.29 modulated PGE2-binding dissociation kinetics, indicative allosteric binding mode. Consistently, antagonized EP4-mediated relaxation piglet saphenous vein rings, partially inhibited cAMP production, but did not affect Gαi activation β-arrestin recruitment. In vivo, significantly improved cisplatin- occlusion-induced models. increased mRNA expression heme-oxygenase 1, Bcl2, FGF-2 cortex; correspondingly, EP4-transfected HEK293 cells, augmented abrogated EP4-dependent overexpression inflammatory IL-6 apoptotic death domain-associated protein BCL2-associated agonist cell death. Our results demonstrate represents novel class diuretic agent with noncompetitive modulator effects on resulting integrity acute failure.