The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 ameliorates ischemic acute renal failure
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Abstract:
Objective: Here we investigate the effects of the endogenous prostaglandin D2 metabolite 15-deoxy-Δ12,14-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-Δ12,14-prostaglandin J2 (1 mg/kg, intravenously) 5 min prior to and again after 3 or 12 h reperfusion. Results: 15-deoxy-Δ12,14-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 γ-glutamyltransferase (γ-GT)) and (iii) histological evidence of renal injury. 15-deoxy-Δ12,14-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-Δ12,14-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 IκB-α degradation revealed that 15-deoxy-Δ12,14-prostaglandin J2 inhibited the activation of nuclear factor (NF)-κB 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-γ and bacterial lipopolysaccharide (LPS) in combination. Conclusions: We demonstrate here, for the first time, that 15-deoxy-Δ12,14-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-κB.Keywords:
Renal ischemia
Dinoprostone
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Catabolism
Prostaglandin E2 receptor
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The in vitro synthesis of prostaglandins E 2 and F 2a by renal cortex, medulla and papilla was measured in normal rats and in rats receiving either a low or a high sodium intake for 14 days.The production of both prostaglandins was unchanged in the cortex.In the medulla, both low and high sodium intakes led to a similar decrease in prostaglandin E 2 synthesis in vitro, but prostaglandin F 2ot synthesis was unchanged.In the papilla, a low sodium intake increased prostaglandin E 2 synthesis.The activity of prostaglandin E 2 9-ketoreductase, a cytosolic enzyme catalysing the conversion of prostaglandin E 2 to prostaglandin F 2a , was unchanged in cortical preparations.In medullary slices, prostaglandin E 2 9ketoreductase activity was decreased by both sodium depletion and loading.In the papilla, prostaglandin E 2 9-ketoreductase activity was slightly decreased by sodium loading and increased with sodium depletion.These results obtained in the rat are at variance with findings in the rabbit.The role played by prostaglandin E 2 9-ketoreductase in the regulation of prostaglandin biosynthesis during changes of sodium balance remains controversial.* ™ .ι Λ-c / * ι Λ ^ .•9a,Ha,15-Trihydroxy-prosta-5,13-dienoate:NADP + ll-oxi-6).The prostaglandin E 2 /prostaglandm F 2a ratio is doreductase (EC 1.1.1189) considered to be regulated by both the synthesis and Renin; Angiotensin forming enzyme (EC 3.4.23.15)
Renal papilla
Renal medulla
Renal cortex
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Amnion
Decidua
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Decidua
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The effect of exposure to oxygen on lung metabolism of prostaglandin E2 to 15-keto-prostaglandin E2 and 13-14-dihydro-15-keto-prostaglandin E2 was studied in the isolated, perfused rat lung. During a 30-sec period, lungs were infused with varying concentrations of prostaglandin E2 labeled with hydrogen-3 and the fraction metabolized during one passage was determined. At a prostaglandin E2 concentration of 5 nM, which approximates that in normal mixed venous blood, an average of 93 per cent of infused prostaglandin was metabolized by normal lungs. At prostaglandin E2 concentrations of 2 to 70 micrometer, the fraction metabolized decreased. The computed concentration of prostaglandin E2 for half-maximal rate of metabolism was 4.2 micrometer. Metabolism of prostaglandin E2 by isolated lungs was unaffected by exposure of rats to greater than 97 per cent oxygen at 1 atmosphere absolute for 24 hours, but was markedly depressed after both 36 and 48 hours of hyperoxia. These results indicate that exposure of the rat to oxygen for 36 and 48 hours is associated with decreased ability of the lung to metabolize prostaglandin E2 to its keto derivatives and may result in increased concentration of prostaglandin E2 in the systemic arterial blood.
Hyperoxia
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Arterial blood
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Treatment of spleen cells derived from adult thymectomized mice with thymosin fraction 5 resulted in a rapid and dose-dependent stimulation of the release of immunoreactive prostaglandin E2. The release of prostaglandin E2 was associated with induction of theta antigen and was totally inhibited by indomethacin. In contrast, prostaglandin E2 release from spleen cells from intact donors was inhibited by treatment with fraction 5. The data support the concept that prostaglandin E2 mediates the effects of thymosin fraction 5 on lymphocytes.
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Prostaglandin E2 receptor
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