Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats
Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats
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DOI：
10.1172/jci32636
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Mochly-Rosen, Daria
中科院分区：
文献类型：
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作者：
Qi, Xin;Inagaki, Koichi;Mochly-Rosen, Daria
高血压脑病是一种与脑水肿和血脑屏障（BBB）破坏相关的潜在致命性疾病。然而，导致这种情况的分子途径尚不清楚。我们使用 delta V1-1（一种 delta PKC 的选择性肽抑制剂）确定了 delta PKC（被认为调节微血管通透性）在高血压脑病发展中的作用。作为高血压脑病模型，Dahl 盐敏感大鼠从 6 周龄开始饲喂 8% 高盐饮食，然后进行皮下注射。使用渗透微型泵，用盐水、对照 TAT 肽或 delta V1-1 进行检测。与对照组相比，Delta V1-1治疗组的死亡率和高血压脑病行为症状显着降低，血脑屏障通透性降低60%以上。 delta V1-1 治疗还与毛细血管内皮细胞和毛细血管星形胶质细胞末端的 delta PKC 积累减少有关，这表明微血管破坏减少。 Delta V1-1 治疗可预防高血压引起的与 BBB 破坏相关的紧密连接破坏，这表明 delta PKC 可能专门导致紧密连接成分失调。总之，这些结果表明 delta PKC 在高血压诱发的脑病的发展中发挥作用，并且可能是预防 BBB 破坏的治疗靶点。
Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of delta PKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using delta V1-1 - a selective peptide inhibitor of delta PKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or delta V1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the delta V1-1-treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with delta V1-1 was also associated with decreased delta PKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with delta V1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that delta PKC may specifically act to dysregulate tight junction components. Together, these results suggest that delta PKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.