Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China.
Basic Medical College, Jiamusi University, Jiamusi, 154007, Heilongjiang, China.
Cardiovasc Toxicol. 2024 Sep;24(9):904-917. doi: 10.1007/s12012-024-09888-9. Epub 2024 Jul 15.
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.
高血压是一种全球普遍存在的疾病，但发病机制仍不清楚。AMP 激活的蛋白激酶（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。之前，我们发现高血压大鼠下丘脑室旁核（PVN）中磷酸化（p-）形式的 AMPK 下调，血管紧张素 II 型 1 型受体（AT1-R）上调，p-ERK1/2 上调。然而，在高血压期间，PVN 中 AMPK 与 AT1-R 之间的确切关系的具体机制尚不清楚。因此，我们假设 AMPK 通过 PVN 中的 ERK1/2-NF-κB 途径调节 AT1-R，从而抑制交感神经活性并改善高血压。为了检验这一假设，我们采用两肾一夹（2K1C）和假手术（SHAM）建立的肾血管性高血压动物模型。人工脑脊液（aCSF），用作载体，或 5-氨基-1-β-D-核糖呋喃基-咪唑-4-羧酰胺（AICAR，AMPK 激活剂，60μg/天）双侧注入这些大鼠的 PVN 中 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，高血压大鼠的 p-AMPK 和 p-AMPK/AMPK 表达降低，p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 表达升高，PVN 中 NF-κB p65 活性高于 SHAM 大鼠的水平。4 周双侧 PVN 注射 AMPK 激活剂 AICAR，减轻了 NE 水平和 SBP，增加了 p-AMPK 和 p-AMPK/AMPK 的表达，减轻了 NF-κB p65 活性，减少了 p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 在 2K1C 大鼠 PVN 中的表达。本研究的数据表明，PVN 内 AMPK 的激活通过抑制 ERK1/2-NF-κB 途径抑制 AT1-R 表达，降低交感神经系统活性，改善高血压。
