Hypoxia-inducible factor-1alpha signaling in aquaporin upregulation after traumatic brain injury.
Hypoxia-inducible factor-1alpha signaling in aquaporin upregulation after traumatic brain injury.
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DOI：
10.1016/j.neulet.2009.01.077
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发表时间：
2009-03-27
影响因子：
2.5
通讯作者：
Rafols JA
中科院分区：
文献类型：
--
作者：
Ding JY;Kreipke CW;Speirs SL;Schafer P;Schafer S;Rafols JA
先前的研究表明，创伤性脑损伤（TBI）通过水通道蛋白（AQP）（水转运蛋白）引起脑水肿。在本研究中，我们确定了缺氧诱导因子-1α（HIF-1α）（一种响应生理缺氧的转录因子）在调节 AQP4 和 AQP9 表达中的作用。成年雄性Sprague-Dawley大鼠（400-425g）使用Marmarou体重下降模型以450g的重量接受闭合性头部损伤，并存活1、4、24和48小时。一些动物在受伤后 30 分钟接受 2-甲氧基雌二醇 (2ME2)（一种雌二醇的天然代谢物，已知可在转录后下调 HIF-1α 表达），并在受伤后 4 小时处死。实时荧光定量PCR和Western blot分别检测锰超氧化物歧化酶（MnSOD，显示缺氧应激）、HIF-1α、AQP4和AQP9的基因和蛋白表达。方差分析表明，从损伤后 1 小时开始直至 48 小时，MnSOD、HIF-1α、AQP4 和 AQP9 的基因表达显着增加（p<0.05）。蛋白质印迹分析进一步表明这些分子在同一时间点的蛋白质表达显着增加（p<0.05）。 2ME2 对 HIF-1α 的药理抑制可降低 TBI 后 AQP4 和 AQP9 的上调水平。本研究表明，闭合性颅脑损伤后由 MnSOD 表达决定的缺氧条件有助于 HIF-1α 的表达。 HIF-1α 反过来又上调 AQP4 和 AQP9 的表达。这些结果描述了病理生理学机制的特征，并为 TBI 患者提出了可能的治疗靶点。
Previous studies have demonstrated that traumatic brain injury (TBI) causes brain edema via aquaporins (AQPs), the water transporting proteins. In the present study, we determined the role of hypoxia inducible factor-1α (HIF-1α), which is a transcription factor in response to physiological hypoxia, in regulating expression of AQP4 and AQP9. Adult male Sprague-Dawley rats (400–425g) received a closed head injury using the Marmarou weight drop model with a 450 g weight and survived for 1, 4, 24 and 48 hours. Some animals were administered 30 minutes after injury with 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol which is known to post-transcriptionally down-regulate HIF-1α expression, and sacrificed 4 hours after injury. Real-time PCR and Western blot were used, respectively, to detect gene and protein expressions of manganese superoxide dismutase (MnSOD, showing hypoxic stress), HIF-1α, AQP4, and AQP9. ANOVA analysis demonstrated a significant (p<0.05) increase in gene expression of MnSOD, HIF-1α, AQP4, and AQP9, starting at 1 hour after injury through 48 hours. Western blot analysis further indicated a significant (p<0.05) increase in protein expression of these molecules at the same time points. Pharmacological inhibition of HIF-1α by 2ME2 reduced the up-regulated levels of AQP4 and AQP9 after TBI. The present study suggests that hypoxic conditions determined by MnSOD expression after closed head injury contribute to HIF-1α expression. HIF-1α, in turn, up-regulates expression of AQP4 and AQP9. These results characterize the pathophysiological mechanisms, and suggest possible therapeutic targets for TBI patients.
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