Repetitive hypoxic preconditioning attenuates renal ischemia/reperfusion induced oxidative injury via upregulating HIF-1 alpha-dependent bcl-2 signaling.
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.
Yang
Chih-Ching
CC
Department of Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Lin
Lung-Ching
LC
Wu
Ming-Shiou
MS
Chien
Chiang-Ting
CT
Lai
Ming-Kuen
MK
D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008928:Mitochondria / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D018384:Oxidative Stress; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D011064:Poly Adenosine Diphosphate Ribose; D045304:Cytochromes c; D003404:Creatinine; C505410:Casp3 protein, rat; D053148:Caspase 3