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

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.
AuthorsMartin Leduc, Xin Hou, David Hamel, Melanie Sanchez, Christiane Quiniou, Jean-Claude Honoré, Olivier Roy, Ankush Madaan, William Lubell, Daya R Varma, Joseph Mancini, François Duhamel, Krishna G Peri, Vincent Pichette, Nikolaus Heveker, Sylvain Chemtob
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 304 Issue 1 Pg. R10-22 (Jan 1 2013) ISSN: 1522-1490 [Electronic] United States
PMID23152113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • (4,4)-biphenylalanyl-threonyl-seryl-tyrosyl-glutamyl-alanyl-leucyl-lysyl-lysine
  • Interleukin-6
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Prostaglandin E, EP4 Subtype
  • Fibroblast Growth Factor 2
  • Cyclic AMP
  • Heme Oxygenase-1
  • Cisplatin
  • Acute Kidney Injury (chemically induced, drug therapy, pathology)
  • Animals
  • Cisplatin (adverse effects)
  • Cyclic AMP (biosynthesis)
  • Disease Models, Animal
  • Dogs
  • Female
  • Fibroblast Growth Factor 2 (biosynthesis)
  • Glomerular Filtration Rate (drug effects)
  • HEK293 Cells
  • Heme Oxygenase-1 (biosynthesis)
  • Humans
  • Interleukin-6 (biosynthesis)
  • Kidney (drug effects, physiology)
  • Male
  • Oligopeptides (therapeutic use)
  • Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP4 Subtype (agonists)
  • Recovery of Function (drug effects)
  • Renal Plasma Flow (physiology)
  • Saphenous Vein (drug effects, pathology)
  • Swine (physiology)

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