Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as compared to pre-menopausal females. It is well documented that in various experimental models of hypertension, the protection against hypertension in females is lost following ovariectomy (OVX). Recently we have shown that CYP1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol (2-ME). This study was conducted to determine if 2-ME reduces Ang II-induced hypertension, renal dysfunction and end organ damage in OVX female, and intact male mice. Treatment of OVX
Cyp1b1
+/+
and
Cyp1b1
-/-
female mice with 2-ME (1.5 mg/kg/day i.p., for 2 weeks) reduced Ang II-induced increase in systolic blood pressure (SBP) (182±5.1 vs. 143± 2.4 mmHg, 179±6.4 vs. 140± 8.6 mmHg, P < 0.05, n= 5), water consumption, urine output and osmolality, and proteinuria (5.5±0.7 vs. 3.3±0.5 mg/24 hrs, 8.4±1.3 vs. 4.4 ±0.9 mg/24 hrs) respectively. 2-ME also reduced Ang II-induced increase in SBP (188±2.6 vs. 143± 2.7 mmHg, P < 0.05, n= 5) in intact male mice. 2-ME did not alter water consumption and urine osmolality, but reduced urine output and sodium excretion, and proteinuria (14.4±2.0 vs. 6.0±0.5 mg/24 hrs) in intact
Cyp1b1
+/+
male mice. Treatment with 2-ME attenuated Ang II-induced end-organ damage (actin and collagen accumulation) in OVX
Cyp1b1
+/+
and
Cyp1b1
-/-
female and
Cyp1b1
+/+
male mice. 2-ME mitigated urinary excretion of angiotensinogen in OVX
Cyp1b1
+/+
and
Cyp1b1
-/-
female mice infused with Ang II. These data suggest that 2-ME reduces Ang II- induced hypertension and associated renal dysfunction and end-organ damage in OVX
Cyp1b1
+/+
and
Cyp1b1
-/-
female, and intact male mice. Therefore, 2-ME could serve as a therapeutic agent for treatment of hypertension and associated pathogenesis in post-menopausal females, and intact males.