Document Detail


Restoration of renal function by a novel prostaglandin EP4 receptor-derived peptide in models of acute renal failure.
MedLine Citation:
PMID:  23152113     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Martin 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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-14
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  304     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-03-07     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R10-22     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/(4,4)-biphenylalanyl-threonyl-seryl-tyrosyl-glutamyl-alanyl-leucyl-lysyl-lysine; 0/Interleukin-6; 0/Oligopeptides; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Prostaglandin E, EP4 Subtype; 103107-01-3/Fibroblast Growth Factor 2; E0399OZS9N/Cyclic AMP; EC 1.14.99.3/Heme Oxygenase-1; Q20Q21Q62J/Cisplatin
Comments/Corrections

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