Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity
Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity
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DOI：
10.1161/hypertensionaha.120.16377
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发表时间：
2021-07-01
期刊：
影响因子：
8.3
通讯作者：
Kanasaki, Keizo
中科院分区：
文献类型：
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作者：
Kumagai, Asako;Takeda, Satoru;Kanasaki, Keizo
COMT（儿茶酚- o -甲基转移酶）是一种代谢儿茶酚的酶，需要镁（Mg2+）来维持其活性。低COMT活性导致2-甲氧基雌二醇（2-ME）不足，这是羟基雌二醇的一种生物活性代谢物，可导致高血压疾病，包括先兆子痫。雌激素水平低下会增加盐敏感性高血压（SSH）的风险。SSH与子痫前期互为危险因素；然而，这种相互作用的分子机制尚不清楚。我们研究了Mg2+缺乏和遗传性COMT缺乏对SSH的交互作用，使用了2株具有不同COMT活性的小鼠。在雄性小鼠中，BL6 (C57BL/6J)，一种高活性COMT菌株，无论食物中Mg2+和盐的水平如何，其血压都没有改变；低活性COMT菌株DBA （DBA/2J）在低Mg2+和高盐条件下发生SSH。C57BL/6J菌株COMT抑制也可诱导SSH。2-ME治疗可改善两种模型的SSH。ATR1（血管紧张素II 1型受体）-STE20-SPAK（丝氨酸-脯氨酸-富丙氨酸激酶）-NCC（氯化钠共转运体）轴，与远曲小管钠重吸收相关的分子，在发生SSH的小鼠中被激活。在雌性DBA小鼠中，去卵巢小鼠在与ATR1-SPAK-NCC轴激活相关的低Mg2+下显示SSH；2-ME抑制了所有这些，而假药小鼠的血压在任何干预下都没有改变。我们的研究结果表明，由于2-ME不足，Mg2+不足放大了COMT的低活性，并通过ATR1-SPAK-NCC轴诱导SSH，提示COMT/2-ME缺乏与高血压综合征之间存在新的病理生理作用。
COMT (Catechol-O-methyl transferase), an enzyme that metabolizes catechol, requires magnesium (Mg2+) to maintain its activity. Low COMT activity causes insufficient 2-methoxyestradiol (2-ME), a biologically active metabolite from hydroxyestradiol, which leads to hypertensive disorders, including preeclampsia. Hypoestrogenism increases the risk of salt-sensitive hypertension (SSH). SSH and preeclampsia are risk factors for each other; however, the molecular mechanism of this interaction is unclear. We focused on the interactive effect of Mg2+ insufficiency and genetic COMT deficiency on SSH using 2 strains of mice with genetically distinct COMT activity. In male mice, BL6 (C57BL/6J), a high-activity COMT strain, displayed unaltered blood pressure regardless of the Mg2+ and salt levels in food; DBA (DBA/2J), a low-activity COMT strain, developed SSH under low Mg2+ and high-salt conditions. COMT inhibition in C57BL/6J strain also induced SSH. Treatment with 2-ME ameliorated SSH in both models. The ATR1 (angiotensin II type 1 receptor)-STE20-SPAK (serine-proline alanine-rich kinase)-NCC (sodium chloride cotransporter) axis, molecules associated with sodium reabsorption in distal convoluted tubules, was activated in mice that developed SSH. In female DBA mice, ovariectomized mice displayed SSH under low Mg2+ associated with activation of ATR1-SPAK-NCC axis; 2-ME inhibited all, whereas the blood pressure of sham mice was unaltered regardless of any intervention. Our findings revealed that Mg2+ insufficiency exaggerated the low COMT activity and induced SSH via the ATR1-SPAK-NCC axis due to 2-ME insufficiency, suggesting a new pathophysiological role that links COMT/2-ME deficiency with hypertensive syndrome.