PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia.
The p53 tumor suppressor gene plays a crucial role in mediating apoptotic cell death in renal ischemia-reperfusion injury (IRI). To further elucidate the p53-dependent pathway, we investigated the role of the p53 apoptosis effector related to PMP-22 (PERP), an apoptosis-associated p53 transcriptional target. PERP mRNA and protein are highly induced in the outer medullary proximal tubular cells (PTC) of ischemic kidneys postreperfusion at 3, 12, and 24 h in a p53-dependent manner. In PTC, overexpression of PERP augmented the rate of apoptosis following hypoxia by inducing mitochondrial permeability and subsequent release of cytochrome c, apoptosis-inducing factor (AIF), and caspase 9 activation. In addition, silencing of the PERP gene with short hairpin RNA prevented apoptosis in hypoxia-mediated injury by precluding mitochondrial dysfunction and consequent cytochrome c and AIF translocation. These data suggest that PERP is a key effector of p53-mediated apoptotic pathways and is a potential therapeutic target for renal IRI.
Singaravelu
Kurinji
K
Dept. of Cellular and Integrative Physiology, Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Devalaraja-Narashimha
Kishor
K
Lastovica
Brynn
B
Padanilam
Babu J
BJ
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D015687:Cell Hypoxia; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D010539:Permeability; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013552:Swine; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; C406964:Perp protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; C506434:Casp9 protein, mouse; D053453:Caspase 9