Repetitive hypoxic preconditioning attenuates renal ischemia/reperfusion induced oxidative injury via upregulating HIF-1α-dependent bcl-2 signaling

Chih Ching Yang, Lung Ching Lin, Ming Shiou Wu, Chiang Ting Chien, Ming Kuen Lai

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50 Citations (Scopus)


BACKGROUND: In response to ischemic/hypoxic preconditioning, tissues/organs exhibit protective responses to subsequent and severe ischemic stress. We hypothesized that repetitive hypoxic preconditioning (RHP) may provide long-lasting protection than single preconditioning against ischemia/reperfusion injury in rat kidneys through hypoxia-induced factor (HIF)-1-dependent pathway. METHODS: For RHP induction, female Wistar rats were subjected to intermittent hypoxic exposure (380 Torr) 15 hr/day for 28 days. RESULTS: RHP increased renal HIF-1α mRNA and protein expression and triggered HIF-1α-dependent renal Bcl-2 protein expression in a time-dependent manner. When returning to normoxia, increased RHP exposure prolonged renal Bcl-2 expression. Forty-five minutes of renal ischemia with 4 hr of reperfusion enhanced O2 levels and proapoptotic mechanisms, including enhanced cytosolic Bax translocation to mitochondria, release of cytochrome c to cytosol, activation of caspase 3, poly-(ADP-ribose)-polymerase fragments, tubular apoptosis, blood urea nitrogen, and creatinine level. RHP treatment depressed renal O2 production, mitochondrial Bax translocation and cytochrome c release, and tubular apoptosis. In the primary tubular cultures from RHP-treated kidneys, antisense oligodeoxyribonucleotides of bcl-2 abrogated this protection. CONCLUSIONS: RHP activates an HIF-1α-dependent signaling cascade leading to an increase in Bcl-2 protein expression, an inhibition in cytosolic Bax and mitochondrial cytochrome c translocation, and a hypoxic/ischemia tolerance against renal ischemia/reperfusion injury.

Original languageEnglish
Pages (from-to)1251-1260
Number of pages10
Issue number11
Publication statusPublished - 2009 Dec 1



  • Apoptosis
  • Hypoxia preconditioning
  • Hypoxia-induced factor-1
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Transplantation

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