Prostacyclin-induced peroxisome proliferator-activated receptor-α translocation attenuates NF-κB and TNF-α activation after renal ischemia-reperfusion injury

Hsi Hsien Chen, Tzen Wen Chen, Heng Lin

研究成果: 雜誌貢獻文章

40 引文 斯高帕斯(Scopus)

摘要

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 PPARα in I/R-induced kidney injury. PPAR-α reduced the NF-κB-induced overexpression of TNF-α and apoptosis in cultured kidney cells. In a murine model, pretreating wild-type (WT) mice with a PPAR-α 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-κB activation. By comparison, I/R-induced injury was exacerbated in PPAR-α knockout mice. This indicated that PPAR-α attenuated renal I/R injury via NF-κB-induced TNF-α overexpression. Overexpression of prostacyclin using an adenovirus could also induce PPAR-α translocation from the cytosol into the nucleus to inhibit caspase-3 activation. This prostacyclin/PPAR-α pathway attenuated TNF-α promoter activity by binding to NF-κB. 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-α production. Taken together, our results demonstrate for the first time that prostacyclin induces the translocation of PPAR-α from the cytosol into the nucleus and attenuates NF-κB-induced TNF-α activation following renal I/R injury. Treatments that can augment prostacyclin, PPAR-α, or the associated signaling pathways may ameliorate conditions associated with renal I/R injury.
原文英語
期刊American Journal of Physiology - Renal Physiology
297
發行號4
DOIs
出版狀態已發佈 - 十月 2009

ASJC Scopus subject areas

  • Physiology
  • Urology

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