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Am J Physiol Renal Physiol. 2011 May;300(5):F1130-41. doi: 10.1152/ajprenal.00591.2010. Epub 2011 Feb 9.

p53 target Siva regulates apoptosis in ischemic kidneys.

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  • 1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, 68198-5850, USA.

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.

PMID:
21307125
PMCID:
PMC3094050
DOI:
10.1152/ajprenal.00591.2010
[PubMed - indexed for MEDLINE]
Free PMC Article
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