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

Abstract

Cytochrome P450 1B1 protects against angiotensin II (Ang II)–induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II–induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1 −/− , ovariectomized female, and 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 hours. 2-Methoxyestradiol reduced Ang 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 Ang 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.