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The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 ameliorates ischemic acute renal failure.

AbstractOBJECTIVE:
Here we investigate the effects of the endogenous prostaglandin D2 metabolite 15-deoxy-Delta(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-Delta(12,14)-prostaglandin J2 (1 mg/kg, intravenously) 5 min prior to and again after 3 or 12 h reperfusion.
RESULTS:
15-deoxy-Delta(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-beta-D-glucosaminidase, aspartate aminotransferase (ASP) and gamma-glutamyltransferase (gamma-GT)) and (iii) histological evidence of renal injury. 15-deoxy-Delta(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-Delta(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 IkappaB-alpha degradation revealed that 15-deoxy-Delta(12,14)-prostaglandin J2 inhibited the activation of nuclear factor (NF)-kappaB 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-gamma and bacterial lipopolysaccharide (LPS) in combination.
CONCLUSIONS:
We demonstrate here, for the first time, that 15-deoxy-Delta(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-kappaB.
AuthorsPrabal Kumar Chatterjee, Nimesh S A Patel, Salvatore Cuzzocrea, Paul A J Brown, Keith N Stewart, Helder Mota-Filipe, Domenico Britti, Wolfgang Eberhardt, Josef Pfeilschifter, Christoph Thiemermann
JournalCardiovascular research (Cardiovasc Res) Vol. 61 Issue 3 Pg. 630-43 (Feb 15 2004) ISSN: 0008-6363 [Print] England
PMID14962493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Calcium-Binding Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Synaptotagmin I
  • Intercellular Adhesion Molecule-1
  • Synaptotagmins
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Prostaglandin D2
Topics
  • Animals
  • Calcium-Binding Proteins
  • Cells, Cultured
  • I-kappa B Proteins (analysis)
  • Intercellular Adhesion Molecule-1 (analysis)
  • Interferon-gamma (pharmacology)
  • Ischemia (metabolism, prevention & control)
  • Kidney (chemistry, metabolism)
  • Kidney Diseases (metabolism, prevention & control)
  • Kidney Tubules (drug effects)
  • Lipopolysaccharides (pharmacology)
  • Male
  • Membrane Glycoproteins (analysis)
  • Models, Animal
  • NF-kappa B (metabolism)
  • Nerve Tissue Proteins (analysis)
  • Nitric Oxide (analysis)
  • Nitric Oxide Synthase (analysis)
  • Nitric Oxide Synthase Type II
  • Prostaglandin D2 (analogs & derivatives, pharmacology, therapeutic use)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (metabolism, prevention & control)
  • Synaptotagmin I
  • Synaptotagmins
  • Time Factors

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