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

Abstract

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