Chen Hsi-Hsien, Chen Tzen-Wen, Lin Heng
Graduate Institute of Clinical Medicine, College of Medicine, Taipai Medical University, Taiwan.
Am J Physiol Renal Physiol. 2009 Oct;297(4):F1109-18. doi: 10.1152/ajprenal.00057.2009. Epub 2009 Jul 29.
Prostacyclin and peroxisome proliferator-activated receptors (PPAR) protect against ischemia-reperfusion (I/R) injury by the induction of an anti-inflammatory pathway. In this study, we examined the prostacyclin-enhanced protective effect of PPARalpha in I/R-induced kidney injury. PPAR-alpha reduced the NF-kappaB-induced overexpression of TNF-alpha and apoptosis in cultured kidney cells. In a murine model, pretreating wild-type (WT) mice with a PPAR-alpha activator, docosahexaenoic acid (DHA), significantly reduced I/R-induced renal dysfunction (lowered serum creatinine and urea nitrogen levels), apoptotic responses (decreased apoptotic cell number and caspase-3, -8 activation), and NF-kappaB activation. By comparison, I/R-induced injury was exacerbated in PPAR-alpha knockout mice. This indicated that PPAR-alpha attenuated renal I/R injury via NF-kappaB-induced TNF-alpha overexpression. Overexpression of prostacyclin using an adenovirus could also induce PPAR-alpha translocation from the cytosol into the nucleus to inhibit caspase-3 activation. This prostacyclin/PPAR-alpha pathway attenuated TNF-alpha promoter activity by binding to NF-kappaB. Using a cAMP inhibitor (CAY10441) and a prostacyclin receptor antibody, we also found that there was another prostacyclin/IP receptor/cAMP pathway that could inhibit TNF-alpha production. Taken together, our results demonstrate for the first time that prostacyclin induces the translocation of PPAR-alpha from the cytosol into the nucleus and attenuates NF-kappaB-induced TNF-alpha activation following renal I/R injury. Treatments that can augment prostacyclin, PPAR-alpha, or the associated signaling pathways may ameliorate conditions associated with renal I/R injury.
前列环素和过氧化物酶体增殖物激活受体（PPAR）通过诱导抗炎途径来预防缺血再灌注（I/R）损伤。在本研究中，我们检测了前列环素增强PPARα对I/R诱导的肾损伤的保护作用。PPARα可减少核因子κB（NF-κB）诱导的培养肾细胞中肿瘤坏死因子α（TNF-α）的过表达和细胞凋亡。在小鼠模型中，用PPARα激活剂二十二碳六烯酸（DHA）预处理野生型（WT）小鼠，可显著减轻I/R诱导的肾功能障碍（降低血清肌酐和尿素氮水平）、凋亡反应（减少凋亡细胞数量以及半胱天冬酶-3、-8的激活）和NF-κB激活。相比之下，I/R诱导的损伤在PPARα基因敲除小鼠中加剧。这表明PPARα通过NF-κB诱导的TNF-α过表达减轻肾I/R损伤。使用腺病毒过表达前列环素也可诱导PPARα从细胞质转位至细胞核以抑制半胱天冬酶-3的激活。这种前列环素/PPARα途径通过与NF-κB结合减弱TNF-α启动子活性。使用环磷酸腺苷（cAMP）抑制剂（CAY10441）和前列环素受体抗体，我们还发现存在另一条可抑制TNF-α产生的前列环素/IP受体/cAMP途径。综上所述，我们的结果首次证明前列环素可诱导PPARα从细胞质转位至细胞核，并在肾I/R损伤后减弱NF-κB诱导的TNF-α激活。能够增强前列环素、PPARα或相关信号通路的治疗方法可能会改善与肾I/R损伤相关的病症。
