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 (Mg 2+ ) 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 Mg 2+ 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 Mg 2+ and salt levels in food; DBA (DBA/2J), a low-activity COMT strain, developed SSH under low Mg 2+ 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 Mg 2+ 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 Mg 2+ 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.

2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A 2 α Activity in Female Mice

“…46,47 2-ME also inhibits activation and proliferation of T and B cells and production of cytokines in vitro and in a model of autoimmune encephalomyelitis. 48 Since cPLA 2 α is also required for L-NAME-induced hypertension and its associated endothelial dysfunction, 49 and deoxycorticosterone salt-induced hypertension (Song and Malik, unpublished work), isolevuglandins are formed from AA, 50 47,[51][52][53][54][55] all of which could be due to its inhibitory effect on cPLA 2 α activity and generation of eicosanoids that have been implicated in these disorders remains to be explored.…”

“…Moreover, the contribution of renal sodium transport and renal vascular function to the eicosanoid-mediated effect of 2-ME in lowering Ang II–induced increased BP in ovariectomized- and Cyp1b1 gene disrupted mice remains to be determined. Finally, the protective effects of 2-ME on pressure-dependent and independent cardiac hypertrophy and fibrosis and renal injury, lowering cholesterol levels, reducing neointimal growth, angiogenesis, pulmonary hypertension, and preeclampsia, magnesium insufficiency–induced salt-sensitive hypertension with reduced catechol- O -methyltransferase activity, and anticarcinogenic actions 47,51–55 all of which could be due to its inhibitory effect on cPLA 2 α activity and generation of eicosanoids that have been implicated in these disorders remains to be explored.…”

Mg 2+ Channels as the Link Between Mg 2+ Deficiency and COMT Downregulation in Salt-Sensitive Hypertension

“…Notwithstanding some of the unanswered questions in the study by Kumagai et al, 15 the novel findings delineate a novel mechanism whereby downregulation of Mg 2+ -regulated COMT/2-ME and consequent increased signaling through SPAK/NCC underlies salt-sensitive hypertension. Normalization of these processes by Mg 2+ underscores a potential beneficial role of Mg 2+ supplementation.…”

“…The rationale for this is based on the fact that (1) COMT has an obligatory need for Mg 2+ for its enzymatic activation, 14 (2) preeclampsia is an Mg 2+ -sensitive disorder, 3 and (3) hypomagnesemia has been demonstrated in experimental and clinical hypertension, especially salt-sensitive hypertension. 3 In the current issue, Kumagai et al 15 further develop this thesis by studying interactions between COMT, salt-sensitive hypertension, and the role of Mg 2+ as a critical element linking these phenomena. To address this, COMT/2-ME and downstream signaling events were studied in rat models with varying degrees of COMT activity, specifically C57BL/6J (BL6), a high-activity COMT strain, and DBA/2J (DBA), a low-activity COMT strain, administered low Mg 2+ diet followed by high salt intake to induce hypertension.…”

Increased Wnt/β-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis

“…The sham and one DMM group were fed a basal control diet with magnesium content of 500 mg/kg following the recommendations of the American Institute of Nutrition (AIN-93G) [31][32][33]. The other two DMM groups received low magnesium diet with magnesium content of 100 mg/kg [34] and 300 mg/kg [35] according to previous studies, respectively. The diet compositions were shown in Table 1.…”