Department of Physiology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas.
J Neuroendocrinol. 2018 Nov;30(11):e12639. doi: 10.1111/jne.12639. Epub 2018 Oct 14.
High salt loading (SL) is associated with inappropriate arginine vasopressin (AVP) release and increased mean arterial pressure. Previous work has shown that chronic high salt intake impairs baroreceptor inhibition of rat AVP neurones through brain-derived neurotrophic factor (BDNF) dependent activation of tyrosine receptor kinase B (TrkB) and down-regulation of K+/Cl- co-transporter KCC2. This mechanism diminishes the GABA inhibition of AVP neurones in the supraoptic nucleus (SON) by increasing intracellular chloride. However, the source of BDNF leading to this ionic plasticity is unknown. In the present study, we used adeno-associated viral vectors with short hairpin RNA against BDNF to test whether SON is the source of BDNF contributing to increased AVP release and elevated mean arterial pressure in high salt loaded rats. Virally mediated BDNF knockdown (shBDNF) in the SON of salt loaded rats significantly blocked the increases in BDNF mRNA and AVP heterogeneous RNA expression. The observed increase in the activation of TrkB receptor during salt loading is consistent with previous studies. Western blot analysis of SON punches revealed that tyrosine phosphorylation of TrkB (pTrkBY515) was significantly decreased in salt shBDNF rats compared to the salt scrambled (SCR) rats. Injections of shBDNF in the SON also significantly prevented the increase in plasma AVP concentration associated with salt loading. However, the salt loading induced increase in mean arterial pressure was not decreased with BDNF knockdown in the SON. Average daily fluid intake and urine output were significantly elevated in both salt SCR and salt shBDNF rats compared to the euhydrated controls. Daily average urine sodium concentration was significantly higher in shBDNF injected salt rats than the other groups. These findings indicate that BDNF produced in the SON contributes to the increased AVP secretion during high salt loading but not with respect to the subsequent increase in mean arterial pressure.
高盐负荷（SL）与不适当的精氨酸加压素（AVP）释放和平均动脉压升高有关。先前的工作表明，慢性高盐摄入通过脑源性神经营养因子（BDNF）依赖性激活酪氨酸受体激酶 B（TrkB）和下调 K + / Cl - 共转运蛋白 KCC2 来损害大鼠加压素神经元的压力感受器抑制。这种机制通过增加细胞内氯离子来减弱视上核（SON）中 AVP 神经元的 GABA 抑制。然而，导致这种离子可塑性的 BDNF 来源尚不清楚。在本研究中，我们使用针对 BDNF 的短发夹 RNA 腺相关病毒载体来测试 SON 是否是导致盐负荷大鼠 AVP 释放增加和平均动脉压升高的 BDNF 来源。盐负荷大鼠 SON 中的病毒介导 BDNF 敲低（shBDNF）显著阻断了 BDNF mRNA 和 AVP 异质 RNA 表达的增加。在盐负荷过程中观察到的 TrkB 受体激活增加与先前的研究一致。SON 打孔的 Western blot 分析显示，与盐 SCR 大鼠相比，盐 shBDNF 大鼠中 TrkB 受体的酪氨酸磷酸化（pTrkBY515）显著降低。SON 中的 shBDNF 注射也显著阻止了与盐负荷相关的血浆 AVP 浓度的增加。然而，SON 中的 BDNF 敲低并没有降低盐负荷引起的平均动脉压升高。与正常水合对照组相比，盐 SCR 和盐 shBDNF 大鼠的平均每日液体摄入量和尿量均显著升高。shBDNF 注射盐大鼠的每日平均尿钠浓度明显高于其他组。这些发现表明，SON 中产生的 BDNF 有助于在高盐负荷期间增加 AVP 的分泌，但与随后的平均动脉压升高无关。
