15-Deoxy-Delta(12,14)-prostaglandin J(2) induces mitochondrial-dependent apoptosis through inhibition of PKA/NF-kappaB in renal proximal epithelial cells.
We have previously reported the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) induces renal proximal epithelial cell death through NF-kappaB inhibition. However, the upstream and down-stream signaling pathways that NF-kappaB inhibition mediates 15d-PGJ(2)-induced apoptosis remain to be defined. In the present study, we determined whether NF-kappaB inhibition induces cell death through the mitochondrial apoptotic pathway and whether protein kinase A (PKA) functions upstream of NF-kappaB inhibition by 15d-PGJ(2). The role of NF-kappaB inhibition in this apoptotic pathway was evaluated using NF-kappaB p65 transfected cells. 15d-PGJ(2) induced cell death by a PPARgamma-independent mechanism and the cell death was prevented by NF-kappaB p65 transfection. 15d-PGJ(2) treatment caused disruption of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation, suggesting that 15d-PGJ(2) induces cell death through a mitochondria-dependent apoptotic mechanism. These changes by 15d-PGJ(2) were attenuated by NF-kappaB p65 transfection. 15d-PGJ(2) treatment resulted in an increase in Bax expression, which were blocked by NF-kappaB p65 transfection. 15d-PGJ(2) treatment caused PKA inhibition and 15d-PGJ(2)-induced cell death was enhanced by the PKA specific inhibitor H89. Inhibition of NF-kappaB by 15d-PGJ(2) was prevented by addition of forskolin, a PKA activator. Taken together, these results suggest that PKA-dependent NF-kappaB inhibition stimulates 15d-PGJ(2)-mediated mitochondrial apoptotic pathway through alterations in expression of the NF-kappaB target genes Bax.
Lee
Dong Ryeol
DR
Department of Physiology, College of Medicine, Pusan National University, Pusan 602-739, Republic of Korea.
Kwon
Chae Hwa
CH
Park
Ji Yeon
JY
Kim
Yong Keun
YK
Woo
Jae Suk
JS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D045304:Cytochromes c / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017930:Genes, Reporter; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D009893:Opossums; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D016328:NF-kappa B; D045304:Cytochromes c; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D020169:Caspases; D015230:Prostaglandin D2