© 2004 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The cyclopentenone prostaglandin 15-deoxy-
12,14-prostaglandin J2 ameliorates ischemic acute renal failure
aDepartment of Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Queen Mary-University of London, Charterhouse Square, London EC1M 6BQ, UK
bDepartment of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
cDepartment of Pathology, University of Aberdeen, Aberdeen, UK
dDepartment of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK
eLaboratory of Pharmacology, University of Lisbon, Lisbon, Portugal
fDepartment of Veterinary and Agricultural Science, University of Teramo, Teramo, Italy
gPharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany
* Corresponding author. Tel.: +44-20-7882-6118; fax: +44-20-7251-1685. c.thiemermann{at}qmul.ac.uk
1 Present address: Department of Pharmacology, School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
Objective: Here we investigate the effects of the endogenous prostaglandin D2 metabolite 15-deoxy-
12,14-prostaglandin J2, on the renal dysfunction and injury caused by ischemia/reperfusion of the kidney. Methods: Male Wistar rats, subjected to bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h, were administered 15-deoxy-12,14-prostaglandin J2 (1 mg/kg, intravenously) 5 min prior to and again after 3 or 12 h reperfusion. Results: 15-deoxy-12,14-prostaglandin J2 significantly reduced (i) renal and tubular dysfunction (serum urea and creatinine levels, creatinine clearance, fractional excretion of Na+ (FENa)), (ii) tubular and reperfusion-injury (urinary N-acetyl-β-D-glucosaminidase, aspartate aminotransferase (ASP) and 
-glutamyltransferase (-GT)) and (iii) histological evidence of renal injury. 15-deoxy-12,14-prostaglandin J2 also improved renal function (plasma creatinine levels) and reduced the histological signs of renal injury (after 48 h reperfusion). Administration of 15-deoxy-12,14-prostaglandin J2 markedly reduced the expression of inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 during reperfusion (determined using immunohistochemistry). Immunohistochemical analysis of p65 translocation and Western blot analysis of I
B-
degradation revealed that 15-deoxy-12,14-prostaglandin J2 inhibited the activation of nuclear factor (NF)-B in renal cells. Subsequently, 15d-PGJ2 was able to significantly reduce nitric oxide production during renal ischemia/reperfusion and by primary cultures of rat proximal tubular (PT) cells incubated with interferon- and bacterial lipopolysaccharide (LPS) in combination. Conclusions: We demonstrate here, for the first time, that 15-deoxy-12,14-prostaglandin J2 significantly reduces renal ischemia/reperfusion-injury via reduction of pro-inflammatory gene expression during reperfusion subsequent to the inhibition of the activation of NF-B.
KEYWORDS Renal function; Ischemia; Reperfusion; Prostaglandins; Rat
Time for primary review 27 days
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