ABSTRACT
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.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia/metabolism , Kidney Diseases/prevention & control , Kidney/metabolism , Oxidative Stress , Proto-Oncogene Proteins c-bcl-2/metabolism , Reperfusion Injury/prevention & control , Signal Transduction , Animals , Apoptosis , Blood Urea Nitrogen , Caspase 3/metabolism , Cells, Cultured , Creatinine/blood , Cytochromes c/metabolism , Disease Models, Animal , Female , Hypoxia/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Kidney/blood supply , Kidney Diseases/genetics , Kidney Diseases/metabolism , Mitochondria/metabolism , Oligodeoxyribonucleotides, Antisense/metabolism , Poly Adenosine Diphosphate Ribose/metabolism , Protein Transport , Proto-Oncogene Proteins c-bcl-2/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Superoxides/metabolism , Time Factors , Up-Regulation , bcl-2-Associated X Protein/metabolismABSTRACT
Reaction of alkyl, acetoxy, and silyl enol ethers of 3-(organosilyl)cyclohexanone with molecular dioxygen in toluene at 110 degrees C produced the corresponding conjugated enones in yields up to 88% yield. The reaction of the same type failed on replacement of the silyl group at the C-3 position with an isopropyl group. These results indicate the existence of an unprecedented silicon-induced ene-type reaction. Its reaction mechanism, generality, limitations, and exceptions are discussed.