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

Abstract

We tested the hypothesis that CYP1B1 (cytochrome P450 1B1)-17β-estradiol metabolite 2-methoxyestradiol protects against Ang II (angiotensin II)–induced hypertension by inhibiting group IV cPLA 2 α (cytosolic phospholipase A 2 α) activity and production of prohypertensive eicosanoids in female mice. Ang II (700 ng/kg per minute, SC) increased mean arterial blood pressure (BP), systolic and diastolic BP measured by radiotelemetry, renal fibrosis, and reactive oxygen species production in wild-type mice ( cPLA 2 α +/+ /Cyp1b1 +/+ ) that were enhanced by ovariectomy and abolished in intact and ovariectomized -cPLA 2 α –/– /Cyp1b1 +/+ mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA 2 α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E 2 and thromboxane A 2 metabolites were enhanced in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 –/– mice. 2-Methoxyestradiol and arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid attenuated the Ang II–induced increase in SBP, renal fibrosis, reactive oxygen species production, and urinary excretion of prostaglandin E 2 , and thromboxane A 2 metabolites in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 –/– mice. Antagonists of prostaglandin E 2 and thromboxane A 2 receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 –/– mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA 2 α activity, reducing prostaglandin E 2 , and thromboxane A 2 production and stimulating EP1 and EP3 and TP receptors, respectively. Thus, 2-methoxyestradiol and the drugs that selectively block EP1 and EP3 and TP receptors could be useful in treating hypertension and its pathogenesis in females.

2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-β1 and p-ERK1/2 Axis

“…Moreover, 2ME loaded TPGS micelles afforded higher degree of protection when compared with raw 2ME. The observed ant-fibrotic effects gain support by several reports highlighting its anti-fibrotic activities of 2ME in the liver [ 74 ], lung [ 75 ] and kidney [ 76 ]. Thus, it can suggest that 2ME anti-fibrotic activity contributes to its protection against CSA-induced kidney injury.…”

Ovariectomy Via 12/15-lipoxygenase Augments Angiotensin II-Induced Hypertension and Its Pathogenesis in Female Mice

“…Furthermore, Ang II also markedly increased the renal alox15 mRNA expression, plasma 12(S)-HETE without altering 15(S)-HETE levels, and increased 12(S)-HETE in urine in OVX-WT mice compared to intact WT mice, suggesting increased activation of ALOX15 and generation of 12(S)-HETE in the absence of E2 plays a critical role in augmenting the effects of Ang II to increase BP, impair autonomic and renal function, produce renal hypertrophy, fibrosis, and ROS. However, further studies are required to determine if E2 directly or via its cytochrome P450 1B1 (CYP1B1)-generated metabolite 2-methoxyestradiol (2-ME) inhibits ALOX15 activity and/or by reducing cytosolic phospholipase A2 activity 43 decreases the release of arachidonic acid for 12(S)-HETE production by ALOX15 in various cell types including infiltrating macrophages in the kidney. 12(S)-HETE is produced in various kidney tissues including glomeruli, cortical and distal convoluted tubules, macrophages, and platelets.…”