Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension
Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension
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DOI：
10.1152/ajpheart.00822.2016
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发表时间：
2017-12-01
影响因子：
4.8
通讯作者：
Shan, Zhiying
中科院分区：
文献类型：
--
作者：
Huber, Michael J.;Fan, Yuanyuan;Shan, Zhiying
食欲素系统参与精氨酸加压素(AVP)的调节，其过度激活与高血压有关。然而，它在盐敏感型高血压(SSHTN)中的作用尚不清楚。在这里，我们验证了一种假说，即室旁核(PVN)中食欲素系统的过度活动通过增强AVP信号而参与SSHTN。8周龄雄性Dahl盐敏感大鼠(Dahl S)和年龄性别匹配的SD大鼠分别给予高盐(HS；8%氯化钠)和正常盐(NS；0.4%氯化钠)饮食4wk。HS摄入对SD大鼠的平均动脉压(MAP)、增食欲素受体1(OX1R)或OX2R的PVN mRNA水平没有影响，但使PVN AVP mRNA的表达略有增加。高脂饮食可引起Dahl-S大鼠MAP和PVN中OX1R、OX2R和AVP的mRNA水平显著升高。侧脑室注射增食欲素A(0.2nmol)可显著增加SD大鼠室旁核AVP基因的表达水平和免疫反应性。培养的新生SD大鼠下丘脑神经元与增食欲素A孵育后，AVP mRNA表达增加，该作用可被OX1R拮抗剂减弱。此外，侧脑室注射氯化钠溶液(4MU/L)可增加脑脊液Na+浓度，增加下丘脑室旁核OX1R和AVP基因表达水平及免疫反应性。此外，与NS喂养(-4+/-4 mm Hg)麻醉的Dahl S大鼠相比，双侧PVN微量注射氧合酶1受体拮抗剂SB-408124使HS摄入量(-16+/-5 mm Hg)的MAP显著降低。这些结果提示，下丘脑室旁核OX1R活性升高可能通过增强AVP信号而参与SSHTN。我们的结果表明，食欲素系统可能通过增强下丘脑室旁核中的加压素信号而参与盐敏感型高血压的Dahl模型。
The orexin system is involved in argininc vasopressin (AVP) regulation, and its overactivation has been implicated in hypertension. However, its role in salt-sensitive hypertension (SSHTN) is unknown. Here, we tested the hypothesis that hyperactivity of the orexin system in the paraventricular nucleus (PVN) contributes to SSHTN via enhancing AVP signaling. Eight-week-old male Dahl salt-sensitive (Dahl S) and age-and sex-matched Sprague-Dawley (SD) rats were placed on a high-salt (HS; 8% NaCl) or normal-salt (NS; 0.4% NaCl) diet for 4 wk. HS intake did not alter mean arterial pressure (MAP), PVN mRNA levels of orexin receptor 1 (OX1R), or OX2R but slightly increased PVN AVP mRNA expression in SD rats. HS diet induced significant increases in MAP and PVN mRNA levels of OX1R, OX2R, and AVP in Dahl S rats. Intracerebroventricular infusion of orexin A (0.2 nmol) dramatically increased AVP mRNA levels and immunoreactivity in the PVN of SD rats. Incubation of cultured hypothalamus neurons from newborn SD rats with orexin A increased AVP mRNA expression, which was attenuated by OX1R blockade. In addition, increased cerebrospinal fluid Na+ concentration through intracerebroventricular infusion of NaCl solution (4 mu mol) increased PVN OX1R and AVP mRNA levels and immunoreactivity in SD rats. Furthermore, bilateral PVN microinjection of the OX1R antagonist SB-408124 resulted in a greater reduction in MAP in HS intake (-16 +/- 5 mmHg) compared with NS-fed (-4 +/- 4 mmHg) anesthetized Dahl S rats. These results suggest that elevated PVN OX1R activation may contribute to SSHTN by enhancing AVP signaling.NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate the involvement of the orexin system in salt-sensitive hypertension. Our results suggest that the orexin system may contribute to the Dahl model of salt-sensitive hypertension by enhancing vasopressin signaling in the hypothalamic paraventricular nucleus.