Normoxic induction of cerebral HIF-1alpha by acetazolamide in rats: role of acidosis.
Acetazolamide has been recognized as an effective treatment for acute mountain sickness. The efficacy of acetazolamide is related to metabolic acidosis, which promotes chemoreceptors to respond to hypoxic stimuli at altitude. In this study, adult male Sprague-Dawley rats were treated with acetazolamide (100mg/kg or 50mg/kg, I.P.) for 3 days. Primary cultured cortical neurons and PC12 cell lines were exposed to acidosis-permissive (pH 6.5) or standard (pH 7.2) media for 20h. HIF-1alpha and its target genes were assayed by Western blot, real-time PCR, HIF-1 DNA-binding assay and chloramphenicol acetyltransferase reporter gene assay. HIF-1alpha protein level and HIF-1 DNA-binding activities were increased in cerebral cortices of rats treated with acetazolamide. Moreover, the mRNA levels of erythropoietin, vascular endothelial growth factor, and glucose transporter-1 also increased. The HIF-1alpha protein level and activity of HIF-driven chloramphenicol acetyltransferase reporters of cortical neurons and PC12 cells treated with acidosis media were significantly enhanced. We conclude that the normoxic induction of HIF-1alpha and HIF-1 mediated genes by acetazolamide may mediate the effect of acetazolamide in the reduction of symptoms of acute mountain sickness.
Xu
Jiajun
J
Department of Diving Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China.
Peng
Zhaoyun
Z
Li
Runping
R
Dou
Tonghai
T
Xu
Weigang
W
Gu
Guojun
G
Liu
Yun
Y
Kang
Zhimin
Z
Tao
Hengyi
H
Zhang
John H
JH
Ostrowski
Robert P
RP
Lu
Jian
J
Sun
Xuejun
X
D000086:Acetazolamide / Q000494:pharmacology*; D000142:Acidosis, Respiratory / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000532:Altitude Sickness / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D002257:Carbonic Anhydrase Inhibitors; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D000086:Acetazolamide; D010100:Oxygen