Restoration of renal function by a novel prostaglandin EP 4 receptor-derived peptide in models of acute renal failure

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2013-01, Vol.304 (1), p.R10-R22
• Main Authors: Leduc, Martin, Hou, Xin, Hamel, David, Sanchez, Melanie, Quiniou, Christiane, Honoré, Jean-Claude, Roy, Olivier, Madaan, Ankush, Lubell, William, Varma, Daya R., Mancini, Joseph, Duhamel, François, Peri, Krishna G., Pichette, Vincent, Heveker, Nikolaus, Chemtob, Sylvain
• Format: Article
• Language: English
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00138.2012

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. PGE 2 is a lipid hormone mediator abundantly produced in the kidney, where it acts locally to regulate renal function; several studies suggest that modulating EP 4 receptor activity could improve renal function following kidney injury. An optimized peptidomimetic ligand of EP 4 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 PGE 2 -binding dissociation kinetics, indicative of an allosteric binding mode. Consistently, THG213.29 antagonized EP 4 -mediated relaxation of piglet saphenous vein rings, partially inhibited EP 4 -mediated cAMP production, but did not affect Gα i 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 EP 4 -transfected HEK293 cells, THG213.29 augmented FGF-2 and abrogated EP 4 -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 EP 4 receptor, resulting in improved renal function and integrity following acute renal failure.