Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels.
Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels.
复制标题
DOI：
10.1007/s11010-021-04056-x
复制
发表时间：
2021-05
影响因子：
4.3
通讯作者：
Huang W
中科院分区：
文献类型：
--
作者：
Chen Q;Wu Y;Yu Y;Wei J;Huang W
HIV-1反式激活蛋白（达特）可导致紧密连接（TJ）功能障碍和β淀粉样蛋白（Aβ）清除功能障碍，从而导致HIV-1相关性神经认知障碍（HAND）的发生和发展。Rho/ROCK信号通路对神经退行性疾病具有保护作用。然而，Rho/ROCK是否能保护HIV-1 Tat引起的TJ和NEP/Aβ转移受体表达功能障碍的潜在机制尚未阐明。向C57 BL/6小鼠施用无菌盐水（i. p.，100 μL）或Rho激酶抑制剂羟基法舒地尔（HF）（i. p.，10 mg/kg）或HIV-1达特（i. v.，100 μg/kg）或HF 30 min后暴露于HIV-1达特，每日1次，连续7天。通过分光光度计和小鼠脑切片检测伊文思蓝（EB）渗漏。分别采用Western blotting和实时定量聚合酶链反应（qRT-PCR）分析小鼠脑微血管中闭合小带-1（ZO-1）、闭合素（occludin）、NEP、晚期糖基化终产物受体（receptor for advanced glycation end products，RECEPTOR）和低密度脂蛋白受体相关蛋白1（low-density lipoprotein receptor-related protein 1，LRP 1）的蛋白和mRNA水平。小鼠暴露于HIV-1达特可增加EB渗漏量、EB荧光强度、血脑屏障（BBB）渗透性以及RAGE蛋白和mRNA水平，并降低小鼠脑微血管中ZO-1、occludin、NEP和LRP 1的蛋白和mRNA水平。Rho激酶抑制剂HF可减弱上述作用。总而言之，这些结果提供了以下信息：Rho/ROCK信号通路参与了C57 BL/6小鼠大脑中HIV-1 Tat诱导的TJ和NEP/Aβ转移受体表达功能障碍。这些发现揭示了抑制Rho/Rock信号通路在处理HAND中的潜力。
HIV-1 transactivator protein (Tat) induces tight junction (TJ) dysfunction and amyloid-beta (Aβ) clearance dysfunction, contributing to the development and progression of HIV-1-associated neurocognitive disorder (HAND). The Rho/ROCK signaling pathway has protective effects on neurodegenerative disease. However, the underlying mechanisms of whether Rho/ROCK protects against HIV-1 Tat-caused dysfunction of TJ and neprilysin (NEP)/Aβ transfer receptor expression have not been elucidated. C57BL/6 mice were administered sterile saline (i.p., 100 μL) or Rho-kinase inhibitor hydroxyfasudil (HF) (i.p., 10 mg/kg) or HIV-1 Tat (i.v., 100 μg/kg) or HF 30 min before being exposed to HIV-1 Tat once a day for seven consecutive days. Evans Blue (EB) leakage was detected via spectrophotometer and brain slides in mouse brains. The protein and mRNA levels of zonula occludens-1 (ZO-1), occludin, NEP, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in mouse brain microvessels were, respectively, analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Exposure of the mice to HIV-1 Tat increased the amount of EB leakage, EB fluorescence intensity, blood–brain barrier (BBB) permeability, as well as the RAGE protein and mRNA levels, and decreased the protein and mRNA levels of ZO-1, occludin, NEP, and LRP1 in mouse brain microvessels. However, these effects were weakened by Rho-kinase inhibitor HF. Taken together, these results provide information that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-induced dysfunction of TJ and NEP/Aβ transfer receptor expression in the C57BL/6 mouse brain. These findings shed some light on potentiality of inhibiting Rho/Rock signaling pathway in handling HAND.
登录
查看更多内容
影响因子：
5.6
作者：
Liu K;Li Z;Wu T;Ding S
通讯作者：
Ding S
影响因子：
5.3
作者：
Hu YB;Zou Y;Huang Y;Zhang YF;Lourenco GF;Chen SD;Halliday GM;Wang G;Ren RJ
通讯作者：
Ren RJ
影响因子：
2.9
作者：
Akiyama, H;Kondo, H;McGeer, PL
通讯作者：
McGeer, PL
影响因子：
5.6
作者：
Martinez-Bonet, Marta;Angeles Munoz-Fernandez, M.;Alvarez, Susana
通讯作者：
Alvarez, Susana
影响因子：
4.2
作者：
Chen, Lei;Choi, Jeong June;Toborek, Michal
通讯作者：
Toborek, Michal