title: p53 target Siva regulates apoptosis in ischemic kidneys.
abstract: The role of p53 in inducing apoptosis following acute kidney injury is well-established; however, the molecular mechanisms remain largely unknown. We report here that the p53 proapoptotic target Siva and its receptor CD27, a member of the tumor necrosis factor receptor family, are upregulated following renal ischemia-reperfusion injury (IRI). Inhibition of Siva using antisense oligonucleotides conferred functional and morphological protection, and it prevented apoptosis postrenal IRI in mice. Renal IRI in CD27-deficient mice displayed functional protection and partial inhibition of apoptosis, suggesting an incomplete role for CD27 in Siva-mediated apoptosis. To further elucidate mechanisms by which Siva elicits apoptosis, in vitro studies were performed. In Siva-transfected LLC-PK(1)cells, Siva is persistently expressed in the nucleus at 3 h onwards and its translocation to mitochondria and the plasma membrane occurred at 6 h. Moreover, Siva overexpression induced mitochondrial permeability, cytochrome c release, caspase-8 and -9 activation, translocation of apoptosis-inducing factor (AIF) to the nucleus, and apoptosis. Inhibition of Siva in ischemic kidneys prevented mitochondrial release of cytochrome c and AIF. These data indicate that Siva function is pivotal in regulating apoptosis in the pathology of renal IRI. Targeting Siva may offer a potential therapeutic strategy for renal IRI.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, 68198-5850, USA.
authors.forename: Kurinji
authors.initials: K
authors.lastname: Singaravelu
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D015687:Cell Hypoxia; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010539:Permeability; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013552:Swine; D013997:Time Factors; D014162:Transfection; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; C494830:AIFM1 protein, mouse; D011993:Recombinant Fusion Proteins; C484569:Siva protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9