title: 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. 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.
authors.affiliation: Research Center/University Hospital Centre Sainte-Justine, Montréal, Québec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Leduc
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.forename: Melanie
authors.initials: M
authors.lastname: Sanchez
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Olivier
authors.initials: O
authors.lastname: Roy
authors.forename: Ankush
authors.initials: A
authors.lastname: Madaan
authors.forename: William
authors.initials: W
authors.lastname: Lubell
authors.forename: Daya R
authors.initials: DR
authors.lastname: Varma
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: François
authors.initials: F
authors.lastname: Duhamel
authors.forename: Krishna G
authors.initials: KG
authors.lastname: Peri
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002945:Cisplatin / Q000009:adverse effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005919:Glomerular Filtration Rate / Q000187:drug effects; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009842:Oligopeptides / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects*; D017595:Renal Plasma Flow / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects / Q000473:pathology; D013552:Swine / Q000502:physiology
chemical_list: C578684:(4,4)-biphenylalanyl-threonyl-seryl-tyrosyl-glutamyl-alanyl-leucyl-lysyl-lysine; D015850:Interleukin-6; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016222:Fibroblast Growth Factor 2; D000242:Cyclic AMP; D051547:Heme Oxygenase-1; D002945:Cisplatin