2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

Abstract

cytochrome P45 1B1 protects against angiotensin II-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine if 2-methoxyestradiol ameliorates angiotensin II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1−/−, ovariectomized female, and in Cyp1b1+/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 h. 2-Methoxyestradiol reduced angiotensin II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1−/− and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1+/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice but not in Cyp1b1+/+ male mice. The G-protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1+/+ female mice. These data suggest that 2-methoxyestradiol reduces angiotensin II-induced hypertension and associated end-organ damage in intact Cyp1b1−/−, ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males.

2-Methoxyestradiol

“…3 The effects of angiotensin II-induced hypertension and end-organ damage in CYP1B1 +/+ , but not CYP1B1 −/− male mice, were mediated by 6β-hydroxytestosterone. 3 In females, conversion of endogenous 17β-estradiol to 2-methoxyestradiol, but not 4-methoxyestradiol (a 4-hydroxyestradiol product), protected against angiotensin II-induced hypertension and end-organ damage.…”

“…3 The effects of angiotensin II-induced hypertension and end-organ damage in CYP1B1 +/+ , but not CYP1B1 −/− male mice, were mediated by 6β-hydroxytestosterone. 3 In females, conversion of endogenous 17β-estradiol to 2-methoxyestradiol, but not 4-methoxyestradiol (a 4-hydroxyestradiol product), protected against angiotensin II-induced hypertension and end-organ damage. 4 Here, they provide conclusive evidence that 2-methoxyestradiol reduces angiotensin II-induced hypertension and prevents renal dysfunction in intact males and ovariectomized female mice.…”

“…In this issue Pingili et al 3 demonstrate that 2-methoxyestradiol, an endogenous 17β-estradiol metabolite, attenuates angiotensin II-induced hypertension and renal dysfunction in intact male and ovariectomized female CYP1B1 +/+ mice. 3 Previously, using CYP1B1 −/− mice and pharmacological CYP1B1 inhibitor, their team demonstrated that conversion of endogenous 17β-estradiol to 2-methoxyestradiol is essential for counteracting angiotensin II-induced hypertension and endorgan damage (renal and cardiovascular) in female mice. 4 Collectively, their findings provide credence to the original hypothesis that 2-methoxyestradiol mediates the protective actions of 17β-estradiol on cardiovascular and renal system.…”

“…4 Here, they provide conclusive evidence that 2-methoxyestradiol reduces angiotensin II-induced hypertension and prevents renal dysfunction in intact males and ovariectomized female mice. 3 Interestingly, circulating levels of 2-methoxyestradiol are lower in subjects with preeclampsia and inversely correlate with hypertension. 8 Moreover, 2-methoxyestradiol lowers blood pressure induced by deoxycorticosterone acetate salt and attenuates hypertension in spontaneously hypertensive and obese ZSF1 rats and in animal models for pulmonary hypertension and renal toxicity.…”

“…8 Moreover, 2-methoxyestradiol lowers blood pressure induced by deoxycorticosterone acetate salt and attenuates hypertension in spontaneously hypertensive and obese ZSF1 rats and in animal models for pulmonary hypertension and renal toxicity. 2,3 The antihypertensive effects of 2-methoxyestradiol were accompanied with improvement in endothelial function and inhibition of vascular, cardiac, renal, and pulmonary remodeling associated with the cell proliferation in the respective diseases. 2,3 Hence, exogenous administration of 2-methoxyestradiol is capable of overriding the deleterious actions of other hydroxyestrogens and quinone/semiquinones,…”