Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms
Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms
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DOI：
10.1161/hypertensionaha.117.09744
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发表时间：
2017-12-01
期刊：
影响因子：
8.3
通讯作者：
Lazartigues, Eric
中科院分区：
文献类型：
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作者：
Sriramula, Srinivas;Lazartigues, Eric
高血压与激肽释放酶-激肽系统的活性增加有关。激肽B1受体（B1 R）激活导致血管收缩和炎症。尽管有证据支持B1 R在血压调节中的作用，但B1 R改变自主神经功能并参与高血压发病机制的机制仍不清楚。我们试图探索B1 R介导的炎症是否有助于高血压，并研究相关的分子机制。在这项研究中，我们测试的假设，激活B1受体在大脑中参与高血压的发病机制，使用脱氧皮质酮醋酸盐模型的神经源性高血压野生型和B1受体基因敲除小鼠。脱氧皮质酮醋酸盐治疗野生型小鼠导致B1 R mRNA和蛋白水平和缓激肽水平显著增加，增强的羧肽酶N基因表达支持B1 R配体的增加，与增强的血压，炎症，交感神经兴奋，自主神经功能障碍和受损的压力反射敏感性，而这些变化在B1 R敲除小鼠中被钝化或阻止。进一步显示B1 R刺激涉及脑中ASK 1-JNK-ERK 1/2和NF-κ B通路的激活。为了消除基因敲除小鼠中潜在的发育改变，我们进一步在野生型小鼠的大脑中选择性地使用B1 R阻断。支持这种机制的中枢起源，脑室内输注特定的B1受体拮抗剂，减弱了脱氧皮质酮醋酸盐诱导的野生型小鼠血压升高。我们的数据提供了B1受体介导的炎症通路在脱氧皮质酮醋酸盐高血压发病机制中的核心作用的第一个证据，并为可能的B1受体靶向治疗神经源性高血压提供了新的见解。
Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-kappa B pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension.