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

Chen HH, Chen TW, Lin H. Prostacyclin-induced peroxisome proliferator-activated receptortranslocation attenuates NFB and TNFactivation after renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 297: F1109–F1118, 2009. First published July 29, 2009; doi:10.1152/ajprenal.00057.2009.—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 PPAR in I/R-induced kidney injury. PPARreduced the NFB-induced overexpression of TNFand apoptosis in cultured kidney cells. In a murine model, pretreating wild-type (WT) mice with a PPARactivator, 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 NFB activation. By comparison, I/R-induced injury was exacerbated in PPARknockout mice. This indicated that PPARattenuated renal I/R injury via NFB-induced TNFoverexpression. Overexpression of prostacyclin using an adenovirus could also induce PPARtranslocation from the cytosol into the nucleus to inhibit caspase-3 activation. This prostacyclin/PPARpathway attenuated TNFpromoter activity by binding to NFB. 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 TNFproduction. Taken together, our results demonstrate for the first time that prostacyclin induces the translocation of PPARfrom the cytosol into the nucleus and attenuates NFB-induced TNFactivation following renal I/R injury. Treatments that can augment prostacyclin, PPAR, or the associated signaling pathways may ameliorate conditions associated with renal I/R injury.