The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion
The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion
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DOI：
10.1111/j.1523-1755.2005.00430.x
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发表时间：
2005-08-01
影响因子：
19.6
通讯作者：
Thiemermann, C
中科院分区：
文献类型：
--
作者：
Collino, M;Patel, NSA;Thiemermann, C
背景我们最近报道，预处理大鼠内毒素（脂多糖，LPS）和选择性激动剂的核受体过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）保护肾脏缺血/再灌注（I/R）损伤。在这里，我们调查的假设，LPS的肾保护作用可能是由于增强形成的内源性配体的过氧化物酶体增殖物激活受体γ，而不是上调的过氧化物酶体增殖物激活受体γ的表达。在不存在（对照）或存在选择性PPAR γ拮抗剂GW 9662（1 mg/kg，IP，缺血前24和12小时）的情况下，用LPS（1 mg/ kg，IP，缺血前24小时）预处理大鼠。注射LPS后24小时，大鼠进行双侧肾缺血60分钟，随后再灌注6小时。测定肾损伤和功能障碍的血清和尿液指标，特别是血清肌酐、天冬氨酸转氨酶和γ-谷氨酰转移酶、肌酐清除率、尿流量和钠排泄分数。通过逆转录-聚合酶链反应测定肾脏PPAR γ 1 mRNA水平。LPS预处理可显著减轻I/R引起的肾损伤和功能障碍的所有标志物。最值得注意的是，GW 9662消除了LPS的保护作用。此外，与假手术组相比，I/R组大鼠肾脏PPAR γ 1 mRNA水平上调，而LPS预处理组大鼠肾脏PPAR γ 1 mRNA水平无明显变化。我们在这里首次证明，内源性配体的过氧化物酶体增殖物激活受体γ可能有助于保护对肾I/R损伤提供LPS预处理大鼠。
Background. We have recently reported that pretreatment of rats with endotoxin ( lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPAR gamma, rather than an up-regulation of PPAR gamma expression.Methods. Rats were pretreated with LPS ( 1 mg/ kg, IP, 24 hours prior to ischemia) in the absence ( control) or presence of the selective PPAR gamma antagonist GW9662 ( 1 mg/ kg, IP, 24 and 12 hours prior to ischemia). Twenty-four hours after injection of LPS, rats were subjected to 60 minutes of bilateral renal ischemia, followed by 6 hours of reperfusion. Serum and urinary indicators of renal injury and dysfunction were measured, specifically serum creatinine, aspartate aminotransferase, and gamma-glutamyl-transferase, creatinine clearance, urine flow, and fractional excretion of sodium. Kidney PPAR gamma 1 mRNA levels were determined by reverse transcriptase-polymerase chain reaction.Results. Pretreatment with LPS significantly attenuated all markers of renal injury and dysfunction caused by I/R. Most notably, GW9662 abolished the protective effects of LPS. Additionally, I/R caused an up-regulation of kidney PPAR gamma 1mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS.Conclusion. We document here for the first time that endogenous ligands of PPAR gamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.