缺氧诱导因子-1α/水通道蛋白4通路在大鼠血脑屏障损伤后高原脑水肿中的作用

邱彩燕 索田莎 林涛 张荣福 李雪玲 孙娟

doi:10.16098/j.issn.0529-1356.2025.02.006

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解剖学报 ›› 2025, Vol. 56 ›› Issue (2) : 163-170. DOI: 10.16098/j.issn.0529-1356.2025.02.006

神经生物学

缺氧诱导因子-1α/水通道蛋白4通路在大鼠血脑屏障损伤后高原脑水肿中的作用

邱彩燕索田莎林涛张荣福李雪玲孙娟*

作者信息 +

Effect of hypoxia inducible factor-1α/aquaporin-4 pathway in high altitude cerebral edema after blood brain barrier damage in rats

QIU Cai-yan SUO Tian-sha LIN Tao ZHANG Rong-fu LI Xue-ling SUN Juan*

Author information +

文章历史 +

摘要

目的探讨缺氧诱导因子1α（HIF-1α）/水通道蛋白4（AQP4）通路在大鼠血-脑屏障损伤后高原脑水肿中的作用。方法 SPF级健康成年雄性SD大鼠（n=40）随机分为2组：对照组（Ctrl，n=20）和高原脑水肿组（HACE，n=20），Ctrl组于青海省西宁市（海拔2261 m）饲养4 d，HACE组于低压模拟舱（海拔5000 m）饲养4 d。干湿重法检测脑水含量，7.0 T小动物磁共振成像（MRI）T2加权像观察颅内结构、形态和信号改变，Nissl染色和TUNEL染色观察大鼠海马组织CA1区神经元形态变化和神经细胞凋亡，免疫组织化学染色观察大鼠海马组织CA1区免疫球蛋白G（IgG）外渗，Western blotting及免疫荧光染色检测大鼠海马组织HIF-1α、AQP4、基质金属蛋白酶9（MMP-9）、紧密连接蛋白5（claudin-5）、闭锁蛋白（occludin）、闭合小环蛋白1（ZO-1）的表达。结果 HACE组大鼠脑水含量明显升高，海马组织CA1区神经元形态萎缩变形，神经元排列紊乱、数量明显下降，神经细胞凋亡明显增加，IgG渗出增多；Western blotting及免疫荧光染色检测发现，海马组织CA1区HIF-1α、AQP4、MMP-9蛋白表达明显升高，claudin-5、occludin、ZO-1蛋白表达明显下降，差异均具有统计学意义（P＜0.05）。结论急性高原低氧通过HIF-1α/AQP4通路导致血-脑屏障破坏，进而导致高原脑水肿。

Abstract

Objective To investigate the effect and mechanism of hypoxia inducible factor-1α/aquaporin-4 (HIF-1α / AQP4) pathway in high altitude cerebral edema (HACE) after blood-brain barrier injury in rats. Methods Adult male SD rats (n= 40) were randomly divided into two groups: control group (Ctrl, n= 20) and high altitude cerebral edema group (HACE, n= 20). The rats in the control group were reared in Xining (altitude 2261m) for 4 days, and the rats in HACE group were reared in low-pressure simulation chamber (altitude 5000m) for 4 days. Brain water content was measured by the method of dry and wet weight. The intracranial structure, morphology and signal changes of small animals were observed through T2 weighted image of 7.0 T MRI. The morphological changes of neurons and the apoptosis of nerve cells in the CA1 region of hippocampal tissue were observed by the staining of Nissl and TUNEL. Immunohistochemical staining was performed to observe the extravasation of immunoglobulin G (IgG). The expressions of HIF-1α, AQP4, matrix metalloproteinase-9 (MMP-9), claudin-5, occludin and zonula occludens-1（ZO-1）in the tissue of hippocampal were detected by the method of Western blotting and immunofluorescent staining. Results The brain water content increased significantly in the HACE group (P < 0.05). The neurons in CA1 region of hippocampal tissue were atrophic and deformed, the arrangement of neurons was disordered in the HACE group. The number of neurons decreased significantly, the apoptosis of nerve cells increased significantly, and the IgG exudates obviously in the CA1 region of hippocampal tissue in the HACE group. The expressions of HIF-1α, AQP4 and MMP-9 proteins increased significantly, while claudin-5, occludin and ZO-1 proteins decreased significantly in the CA1 region of hippocampal tissue, which detected by the method of Western blotting and immunofluorescent staining (P<0.05). Conclusion Acute high-altitude hypoxia can induce to blood-brain barrier disruption through the HIF-1α/AQP4 pathway, resulting in high-altitude cerebral edema.

导出引用

邱彩燕索田莎林涛张荣福李雪玲孙娟. 缺氧诱导因子-1α/水通道蛋白4通路在大鼠血脑屏障损伤后高原脑水肿中的作用[J]. 解剖学报. 2025, 56(2): 163-170 https://doi.org/10.16098/j.issn.0529-1356.2025.02.006

QIU Cai-yan SUO Tian-sha LIN Tao ZHANG Rong-fu LI Xue-ling SUN Juan. Effect of hypoxia inducible factor-1α/aquaporin-4 pathway in high altitude cerebral edema after blood brain barrier damage in rats[J]. Acta Anatomica Sinica. 2025, 56(2): 163-170 https://doi.org/10.16098/j.issn.0529-1356.2025.02.006

中图分类号： R328 R594.3

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