p53 target siva regulates apoptosis in ischemic kidneys

Kurinji Singaravelu, Babu J. Padanilam

Research output: Contribution to journalArticle

19 Citations (Scopus)

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-PK1 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 apoptosisinducing 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.

Original languageEnglish (US)
Pages (from-to)1130-1141
Number of pages12
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number5
DOIs
StatePublished - May 1 2011

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Reperfusion Injury
Apoptosis
Kidney
Cytochromes c
LLC-PK1 Cells
Caspase 9
Caspase 8
Antisense Oligonucleotides
Tumor Necrosis Factor Receptors
Acute Kidney Injury
Permeability
Mitochondria
Cell Membrane
Pathology
Therapeutics

Keywords

  • Acute kidney injury
  • Apoptosis-inducing factor
  • Caspases
  • Cytochrome c
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

p53 target siva regulates apoptosis in ischemic kidneys. / Singaravelu, Kurinji; Padanilam, Babu J.

In: American Journal of Physiology - Renal Physiology, Vol. 300, No. 5, 01.05.2011, p. 1130-1141.

Research output: Contribution to journalArticle

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