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-1 alpha mRNA and protein expression and triggered HIF-1 alpha-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-1 alpha-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.
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-1 alpha mRNA and protein expression and triggered HIF-1 alpha-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 ureanitrogen, 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-1 alpha-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.
Authors: P P Tregub; N A Malinovskaya; E D Osipova; A V Morgun; V P Kulikov; D A Kuzovkov Journal: Neuromolecular Med Date: 2021-06-11 Impact factor: 3.843
Authors: Karla Johanna Ruth Hoyer-Allo; Martin Richard Späth; Ruth Hanssen; Marc Johnsen; Susanne Brodesser; Kathrin Kaufmann; Katharina Kiefer; Felix Carlo Koehler; Heike Göbel; Torsten Kubacki; Franziska Grundmann; Bernhard Schermer; Jens Brüning; Thomas Benzing; Volker Burst; Roman-Ulrich Müller Journal: Int J Mol Sci Date: 2021-05-22 Impact factor: 5.923