Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity

Abstract

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.