Qi Jie, Yu Xiao-Jing, Shi Xiao-Lian, Gao Hong-Li, Yi Qiu-Yue, Tan Hong, Fan Xiao-Yan, Zhang Yan, Song Xin-Ai, Cui Wei, Liu Jin-Jun, Kang Yu-Ming
Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Department of Pharmacology, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Cardiovasc Toxicol. 2016 Oct;16(4):345-54. doi: 10.1007/s12012-015-9344-9.
High-salt-induced inflammation and oxidative stress in the hypothalamic paraventricular nucleus (PVN) contribute to the pathogenesis of salt-sensitive hypertension. In this study, we hypothesized that chronic inhibition of nuclear factor-κB (NF-κB) activity in the PVN delays the progression of hypertension by upregulating anti-inflammatory cytokines, reducing NLRP3 (NOD-like receptor family pyrin domain containing 3) and IL-1β and attenuating p-IKKβ, NF-κB p65 activity and NAD(P)H oxidase in the PVN of salt-sensitive hypertensive rats. Dahl salt-sensitive rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks and were treated with bilateral PVN infusion with either vehicle or pyrrolidine dithiocarbamate (PDTC, 5 μg/h), a NF-κB inhibitor via osmotic minipump. The mean arterial pressure and plasma levels of norepinephrine (NE) and epinephrine (EPI) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of p-IKKβ, NF-κB p65 activity, Fra-like (Fra-LI) activity (an indicator of chronic neuronal activation), NOX-4 (subunits of NAD(P)H oxidase), NLRP3 and IL-1β, and lower levels of IL-10 in the PVN than normal diet rats. Bilateral PVN infusions of PDTC attenuated these high-salt-induced changes. These findings suggest that high-salt-induced NF-κB activation in the PVN caused hypertension via sympathoexcitation, which are associated with the increases of NLRP3, IL-1β and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates NLRP3, IL-1β and oxidative stress in the PVN and thereby attenuates hypertension.
下丘脑室旁核（PVN）中高盐诱导的炎症和氧化应激参与盐敏感性高血压的发病机制。在本研究中，我们假设，慢性抑制PVN中的核因子-κB（NF-κB）活性可通过上调抗炎细胞因子、降低NLRP3（含pyrin结构域的NOD样受体家族3）和白细胞介素-1β（IL-1β）以及减弱盐敏感性高血压大鼠PVN中的磷酸化IκB激酶β（p-IKKβ）、NF-κB p65活性和烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）氧化酶，从而延缓高血压的进展。将Dahl盐敏感性大鼠给予高盐饮食（HS，8%氯化钠）或正常盐饮食（NS，0.3%氯化钠）6周，并通过渗透微型泵经双侧PVN输注载体或吡咯烷二硫代氨基甲酸盐（PDTC，5μg/h，一种NF-κB抑制剂）进行治疗。高盐喂养的大鼠平均动脉压以及去甲肾上腺素（NE）和肾上腺素（EPI）的血浆水平显著升高。此外，与正常饮食大鼠相比，高盐饮食大鼠PVN中的p-IKKβ、NF-κB p65活性、Fra样（Fra-LI）活性（慢性神经元激活指标）、NOX-4（NAD(P)H氧化酶亚基）、NLRP3和IL-1β水平更高，而IL-10水平更低。双侧PVN输注PDTC减弱了这些高盐诱导的变化。这些发现表明，PVN中高盐诱导的NF-κB激活通过交感神经兴奋导致高血压，这与PVN中NLRP3、IL-1β增加以及氧化应激有关；抑制PVN中的NF-κB活性可减弱PVN中的NLRP3、IL-1β和氧化应激，从而减轻高血压。
