Abstract：
Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 μg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.
摘要：
高血压是一种全球流行的疾病，但其发病机制仍不清楚。AMP活化蛋白激酶(AMPK)是细胞能量代谢的营养敏感信号,对高血压的发展有一定的影响。以前,我们发现AMPK的磷酸化（p-）形式下调，以及高血压大鼠下丘脑室旁核（PVN）中血管紧张素II1型受体（AT1-R）和p-ERK1/2的上调。然而,高血压期间PVN中AMPK和AT1-R之间关系的确切机制尚不清楚.因此，我们假设AMPK通过ERK1/2-NF-κB通路在PVN中调节AT1-R，从而抑制交感神经活动，改善高血压。为了检验这个假设，我们采用了一种通过双肾形成的肾血管性高血压动物模型，一个剪辑（2K1C）和假手术（SHAM）。人工脑脊液（aCSF），用作车辆，或5-氨基-1-β-D-呋喃核糖基-咪唑-4-甲酰胺（AICAR，AMPK激活剂，将60μg/天）双侧显微注射到这些大鼠的PVN中，持续4周。在2K1C大鼠中，收缩压（SBP）和循环去甲肾上腺素（NE）升高。此外，高血压大鼠p-AMPK和p-AMPK/AMPK表达降低,p-ERK1/2，p-ERK1/2/ERK1/2和AT1-R的表达升高，与SHAM大鼠中这些生物标志物的水平相比，PVN中NF-κBp65活性增加。双侧PVN注射AMPK激活剂AICAR四周，减弱NE水平和SBP，增加p-AMPK和p-AMPK/AMPK的表达，降低NF-κBp65活性，2K1C大鼠PVN中p-ERK1/2、p-ERK1/2/ERK1/2和AT1-R的表达降低。这项研究的数据表明，PVN中AMPK的激活通过抑制ERK1/2-NF-κB途径抑制了AT1-R的表达，减少了交感神经系统的活动，改善高血压。
