Abstract MP63: Cytochrome P450 1B1 Mediated Inhibition Of Group IV Cytosolic Phospholipase A 2 α In Paraventricular Nucleus Protects Female Mice From Angiotensin II-Induced Hypertension, Increased Renal Sympathetic Activity And Proteinuria

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
ChiYoung Song ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Sympathetic Activity ◽  
Group Iv ◽  
Ang Ii ◽  
Female Mice ◽  
Cytochrome P450 1B1 ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Α Activity ◽  
Renal Sympathetic

Recently we showed that 2-methoxyestradiol (2-ME), an estrogen (E2) metabolite generated by CYP1B1 (cytochrome P450 1B1) in the paraventricular nucleus (PVN), protects female mice from Ang (angiotensin) II-induced hypertension and increased renal sympathetic activity. We also demonstrated that group IV cPLA 2 α (cytosolic phospholipase A 2 α) in the brain contributes to Ang II-induced hypertension in male mice. This study was conducted to determine the contribution of central cPLA 2 α and its relationship to CYP1B1 in Ang II-induced hypertension in female mice. cPLA 2 α knockdown in the PVN by transduction with adenovirus (Ad)-cPLA 2 α-short hairpin (sh)RNA (200 nL, bilaterally, 1.0х10 12 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (2.5х10 11 pfu/mL) in ovariectomized (OVX) wild-type ( cPLA 2 α +/+ / Cyp1b1 +/+ , n=8/group) and intact cPLA 2 α +/+ / Cyp1b1 -/- (n=12/group) female mice attenuated the effect of Ang II (700 ng/kg/min, subcutaneous, osmotic pump, 2 weeks) to increase the systolic blood pressure (SBP, mmHg) as measured by tail-cuff (Day 12: 129±3 vs 168±7 and 119±3 vs 172±5, respectively, P<0.05). Moreover, reconstitution of cPLA 2 α in the PVN by transduction with Ad-cPLA 2 α-DNA (1.1х10 12 pfu/mL) but not its control Ad-GFP-DNA (1.0х10 11 pfu/mL) in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice (n=4/group) restored the effect of Ang II to increase SBP (Day 12: 163±7 vs 124±4, P<0.05). Furthermore, Ad-cPLA 2 α-shRNA but not Ad-Scr-shRNA transduction in the PVN in OVX- cPLA 2 α +/+ / Cyp1b1 +/+ and intact cPLA 2 α +/+ / Cyp1b1 -/- mice reduced and Ad-cPLA 2 α-DNA but not Ad-GFP-DNA transduction in the PVN in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice restored the effect of Ang II to increase the renal sympathetic activity as indicated by urinary norepinephrine level (ng/mL, 324±36 vs 707±94, 359±49 vs 979±70, 690±44 vs 421±43, respectively, n=4/group, P<0.05) and proteinuria (mg/24 hour, 4±1 vs 10±0.4, 3±0.4 vs 7±1, 9±0.8 vs 3±0.7, respectively, n=4/group, P<0.05). These data suggest that E2-CYP1B1 derived metabolite 2-ME protects against Ang II-induced hypertension, renal sympathetic activity, and proteinuria by inhibiting cPLA 2 α activity in the PVN. Thus, 2-ME and/or agents inhibiting cPLA 2 α activity could be useful for treating hypertension and its pathogenesis in females.

Abstract P473: Group IV Cytosolic Phospholipase A2α is Critical for Norepinephrine-Induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Chi Yong Song ◽  
Ji Soo Shin ◽  
Joseph V Bonventre ◽  
Kafait U Malik
Keyword(s):  
Blood Pressure ◽  
Receptor Activation ◽  
Group Iv ◽  
Ang Ii ◽  
Osmotic Pumps ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Pg E2 ◽  
Ep3 Receptor ◽  
Α Activity

Previously we reported that angiotensin (Ang) II-induced hypertension and associated cardiovascular and renal dysfunction are mediated by cytosolic phospholipase A 2 α (cPLA 2 α) activation, the release of arachidonic acid (AA), and production of eicosanoids predominantly with pro-hypertensive effects ( Hypertension. 2015; 65: 784-792; 2016; 29: 258-265 ). We have also shown that norepinephrine (NE) by activating cPLA 2 releases AA, and production of prostanoids in vascular smooth muscle cells ( J Biol Chem. 1996; 217:30149-30157; J. Pharmacol. Exp. Ther. 1993; 266: 1113–1124 ). This study was conducted to determine the contribution of cPLA 2 α in NE-induced hypertension. Eight weeks old male wild-type (cPLA 2 α +/+ ) and cPLA 2 α gene disrupted (cPLA 2 α -/- ) mice were infused with NE (10 mg/kg/day, s.c.) or its vehicle using mini-osmotic pumps for 2 weeks, and the systolic blood pressure (SBP) was measured by tail-cuff. Infusion of NE increased the SBP in cPLA 2 α +/+ mice (148±3 vs. 118±3 mmHg, P<0.05, n=4-5); but not in cPLA 2 α -/- mice (122±5 mmHg, n=5). The NE-induced increase in SBP was minimized by treatment with AA metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid (ETYA) (25 mg/kg, i.p., every 3 rd day) in cPLA 2 α +/+ mice (125±5 vs. 148±3 mmHg, P<0.05, n=4-5). Prostaglandin (PG) E2-EP1 and EP3 receptor activation that increase blood pressure have been implicated in Ang II-induced hypertension. In our study antagonists of the EP3 receptor (L-798106) (10 mg/kg, i.p. every 3 rd day) decreased the NE-induced increase in SBP (130±5 vs. 148±3 mmHg, P<0.05, n=5/group). These data suggest that cPLA 2 α contributes to NE-induced increase in SBP via cPLA 2 α activation, the release of AA and generation of eicosanoids, most likely PGE2 that exerts pro-hypertensive effects by stimulating EP3 receptors. Therefore, the development of agents that selectively inhibit the cPLA 2 α activity or block EP3 receptors could be useful in treating hypertension and its pathogenesis.

Abstract 252: 6ß-Hydroxytestosterone, A Cytochrome P450 1B1 Metabolite of Testosterone, Enhances Angiotensin II-Induced Pressor Effect in Male Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Brett L Jennings ◽  
Nayaab S Khan ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Endothelial Dysfunction ◽  
Ros Production ◽  
Oxygen Species ◽  
Pressor Effect ◽  
Ang Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension ◽  
Novel Target

Androgens have been implicated in the development of hypertension and castration minimizes the pressor effect of angiotensin (Ang) II. Previously we showed that Ang II-induced hypertension and associated pathophysiological changes are diminished in male cytochrome P450 (CYP) 1B1 gene disrupted mice. Since CYP1B1 metabolizes testosterone to 6β-hydroxytestosterone (6β-OHT); this study was conducted to determine its contribution in modulation of Ang II-induced hypertension. Eight weeks old male Cyp1b1+/+ and Cyp1b1-/- mice were either castrated or injected with 6β-OHT (15 μg/g, i.p. every 3rd day) or vehicle (DMSO, 50 μl), infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks, and systolic blood pressure (SBP) was measured by tail cuff. Castration attenuated Ang II-induced increase in SBP in both Cyp1b1+/+ (184 ± 6 vs. 129 ± 4 mmHg, P < 0.05) and Cyp1b1-/- mice (150 ± 6 vs. 129 ± 4 mmHg, P < 0.05). In Cyp1b1+/+ mice, 6β-OHT did not alter Ang II-induced increase in SBP (184 ± 6 vs. 180 ± 8 mmHg, P < 0.05), but enhanced it in Cyp1b1-/- mice (150 ± 6 vs. 172 ± 8 mmHg, P < 0.05). Castration improved endothelial dysfunction associated with Ang II-induced hypertension in Cyp1b1+/+ mice, as demonstrated by increased relaxation of the aorta to acetylcholine. No endothelial dysfunction was observed in Cyp1b1-/- mice given Ang II with or without castration. In Cyp1b1+/+ mice, 6β-OHT did not alter Ang II-induced endothelial dysfunction, however, in Cyp1b1-/- mice infused with Ang II, 6β-OHT caused endothelial dysfunction. We have shown that Ang II-induced hypertension is associated with increased vascular production of reactive oxygen species (ROS) in Cyp1b1+/+ mice, and this increase is attenuated in Cyp1b1-/- mice, as measured by dihydroethidium fluorescence. In both Cyp1b1+/+ and Cyp1b1-/- mice given Ang II, castration abolished the increased ROS production. In Cyp1b1+/+ mice, 6β-OHT did not alter levels of ROS produced by Ang II, however, 6β-OHT further increased ROS production in Cyp1b1-/- mice given Ang II. These data suggest that 6β-OHT, a CYP1B1 metabolite of testosterone, contributes to the hypertensive effect of Ang II in male mice. Moreover, CYP1B1 could serve as a novel target for the development of agents for the treatment of androgen-mediated hypertension.

Abstract 155: Group IV Cytosolic Phospholipase A 2 a Disruption Protects Against Angiotensin II-Induced Hypertension and End Organ Damage

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nayaab S Khan ◽  
Chi Young Song ◽  
Joseph V Bonventre ◽  
Kafait U Malik
Keyword(s):  
Renal Dysfunction ◽  
Water Intake ◽  
Urine Output ◽  
Organ Damage ◽  
Group Iv ◽  
Phospholipase A ◽  
Ang Ii ◽  
End Organ Damage ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension

Previously we have shown that Group IV cytosolic phospholipase A 2 α (cPLA 2 α) is critical for the development of angiotensin (Ang) II-induced hypertension, cardiovascular dysfunction and fibrosis. This study was conducted to determine the role of cPLA 2 α in renal dysfunction and end organ damage associated with Ang II-induced hypertension. Eight weeks old male wild type (cPLA 2 α +/+ ) and cPLA 2 α knockout (cPLA 2 α -/- ) mice were infused with Ang II (700 ng/kg/min) or its vehicle for 2 weeks and systolic blood pressure (SBP) was measured weekly by the tail cuff method. Ang II increased SBP (mmHg) in cPLA 2 α +/+ mice to a greater degree than in cPLA 2 α -/- mice (125 ± 2 to 186 ± 7 vs. 125 ± 2 to 132 ± 2 respectively, P< 0.05). Ang II caused renal fibrosis as indicated by accumulation of α-smooth muscle actin, transforming growth factor-β-positive cells and collagen deposition in the kidneys of cPLA 2 α +/+ but not cPLA 2 α -/- mice. Ang II infusion increased reactive oxygen species production in the kidney measured by 2-hydroxyethidium fluorescence (AU), in cPLA 2 α +/+ mice (16.14 ± 0.61 vehicle vs. 24.08 ± 0.61 Ang II P < 0.05) but not in cPLA 2 α -/- mice (16.93 ± 0.58 vehicle vs. 17.19 ± 0.93 Ang II). Mice were placed in metabolic cages to monitor their water intake and urine output. After 13 days of Ang II infusion, 24 hr water intake was increased (4.33 ± 0.14 ml to 8.17 ± 0.27 ml P < 0.05) in cPLA 2 α +/+ mice but not in cPLA 2 α -/- mice (4.87 ± 0.22 ml to 4.8 ± 0.27 ml). Twenty-four hr urine output (μl) was increased to a greater extent in cPLA 2 α +/+ mice (423.33 ± 67.26 to 2030.94 ± 191.58 P < 0.05) vs. cPLA 2 α -/- mice (374.37 ± 66.89 to 787.37 ± 126.50). Urine osmolality (mOsm/kg) was decreased (3778.33 ± 240.21 to 1620 ± 129.23 P < 0.05) in cPLA 2 α +/+ but not in cPLA 2 α -/- mice (4042 ± 306.07 to 3372.5 ± 43.27), and proteinuria (mg/24hr) increased to a greater extent in cPLA 2 α +/+ mice (2.07 ± 0.11 to 6.99 ± 0.34 P < 0.05) vs. cPLA 2 α -/- mice (1.95 ± 0.07 to 3.03 ± 0.20 in cPLA 2 α -/- ). These data suggest that cPLA 2 α contributes to Ang II-induced hypertension, associated renal dysfunction and end organ damage, most likely due to release of arachidonic acid, activation of NADPH oxidase and generation of ROS. Thus, cPLA 2 α could serve as a potential therapeutic target in the treatment of hypertension and end organ damage.

Abstract 250: 6β-hydroxytestosterone, A Cytochrome P450 1b1-derived Metabolite Of Testosterone, Mediates Increase In Thirst, Renal Dysfunction, And End Organ Damage Associated With Angiotensin II-induced Hypertension In Male Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Mehmet Kara ◽  
Brett L Jennings ◽  
Anne M Estes ◽  
Kafait U Malik
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Cytochrome P450 ◽  
Renal Fibrosis ◽  
Organ Damage ◽  
Ang Ii ◽  
Male Mice ◽  
End Organ Damage ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension

Recently, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Ang II in renal homeostasis and end organ damage, we determined the contribution of 6β-OHT to Ang II actions on water consumption and renal function in male Cyp1b1 +/+ and Cyp1b1 -/- mice. Eight weeks old male Cyp1b1 +/+ and Cyp1b1 -/- intact or castrated mice were injected with 6β-OHT (15 μg/g, i.p. every 3 rd day) or vehicle (DMSO, 50 μl), and infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks. Urine was collected for 24 hours on the final day of experiment. Castration attenuated Ang II-induced increase in water consumption and urine output, proteinuria and decrease in osmolality in both Cyp1b1 +/+ , and Cyp1b1 -/- mice (Table 1). 6β-OHT did not alter Ang II-induced increase in water intake, urine output, proteinuria and decrease in osmolality in Cyp1b1 +/+ mice, but restored these effects of Ang II in Cyp1b1 -/- or castrated mice (Table 1). Cyp1b1 gene disruption or castration prevented Ang II-induced renal fibrosis, inflammation, and oxidative stress. 6β-OHT did not alter Ang II-induced renal fibrosis, inflammation or oxidative stress in Cyp1b1 +/+ mice, however in Cyp1b1 -/- or castrated mice it restored these effects of Ang II. These data suggest that 6β-OHT, contributes to increased thirst, impairment of renal function and end organ damage associated with Ang II-induced hypertension in male mice, and that CYP1B1 could serve as a novel target for the treatment of renal disease and hypertension.

Abstract P012: Cytochrome P450 1B1 Generated 17β-Estradiol Metabolite 2-Methoxyestradiol Inhibits 12/15-Lipoxygenase To Protect Against Angiotensin II-induced Hypertension, Autonomic Dysfunction And Renal Injury In Female Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Renal Injury ◽  
Power Spectral Analysis ◽  
High Frequency Oscillation ◽  
Ang Ii ◽  
Creatinine Ratio ◽  
Albumin Creatinine Ratio ◽  
Female Mice ◽  
Induced Hypertension ◽  
17Β Estradiol

17β-estradiol (E2) via its cytochrome P450 (CYP) 1B1 generated metabolite 2-methoxyestradiol (2ME) protects from angiotensin (Ang) II-induced hypertension in female mice. Gene disruption of 12/15 lipoxygenase (LOX) that metabolizes arachidonate (A) into 12(S)- and 15(S)-HETE minimizes Ang II-induced hypertension in male mice. We performed this study to determine if 2-ME generated by CYP1B1 from E2 mediates its protective effect against Ang II-induced hypertension via LOX inhibition in female mice. Systolic blood pressure (SBP, mmHg, tail-cuff) in response to Ang II (700 ng/Kg/min, sc, miniosmotic pump, 2 weeks) was greater ( P <0.05, n=4-5) in ovariectomized (OVX) than intact Cyp1b1 +/+ / Alox15 +/+ (174±2 vs 135±5), and intact or OVX- Cyp1b1 +/+ / Alox15 –/– (120±4 and 125±5) mice. Moreover, SBP in response to Ang II was greater in trans-2,3',4,5'-tetramethoxystilbene (CYP1B1 inhibitor, 300 μg/Kg, every 3rd day, ip)-treated intact Cyp1b1 +/+ / Alox15 +/+ than Cyp1b1 +/+ / Alox15 –/– (164±3 vs 132±3, n=6-8, P <0.05) mice. Also, mean arterial pressure (MAP, mmHg, radiotelemetry) and low frequency to high-frequency oscillation ratio (LF/HF ratio, power spectral analysis), the index of baroreflex sensitivity impairment, in response to Ang II was greater ( P <0.05, n=4) in OVX- Cyp1b1 +/+ / Alox 15 +/+ (160±3; 2.9±0.1) than in OVX- Cyp1b1 +/+ / Alox15 –/– (119±7; 2±0.1) mice. However, MAP and LF/HF ratio in response to Ang II was lower in 2ME (1.5 mg/g, every 3rd day, ip)-treated OVX- Cyp1b1 +/+ / Alox15 +/+ (108±3; 1.6±0.1) and OVX- Cyp1b1 +/+ / Alox 15 –/– (107±2; 1.6±0.1) mice (n=4). Plasma12(S)-HETE level (ELISA), and renal injury assessed by urine albumin/creatinine ratio in response to Ang II was lower in 2ME than its vehicle (dimethyl sulfoxide)-treated OVX- Cyp1b1 +/+ / Alox 15 +/+ mice (1616±30 vs 2162±55, pg/mL, and 2.7±0.3 vs 1.9±0.1; n=4, P <0.05). Ang II did not increase 12(S)-HETE or albumin/creatinine ratio in Cyp1b1 +/+ / Alo x 15 –/– mice. These data suggest that that E2-CYP1B1 generated metabolite 2ME by inhibiting A-LOX signaling protects against Ang II-induced hypertension, impaired baroreflex, and renal injury in female mice. Therefore, LOX inhibitors could be useful in the treatment of Ang II-induced hypertension and associated renal injury in females.

scholarly journals Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe –/– Male Mice

2021 ◽  
Author(s):  
Kamalika Mukherjee ◽  
Ajeeth K. Pingili ◽  
Purnima Singh ◽  
Ahmad N. Dhodi ◽  
Shubha R. Dutta ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Risk Factor ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Abdominal Aortic ◽  
Induced Hypertension

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe –/– male mice. Methods and Results Intact or castrated Apoe –/– /Cyp1b1 +/+ and Apoe –/– /Cyp1b1 –/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe –/– /Cyp1b1 +/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe –/– /Cyp1b1 –/– mice. Conclusions Our results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe –/– male mice.

Abstract P135: 2-methoxyestradiol Minimizes Angiotensin II-induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Shyamala Thirunavukkarasu ◽  
Nayaab S Khan ◽  
Akemi Katsurada ◽  
Dewan S Majid ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Dysfunction ◽  
Organ Damage ◽  
Ang Ii ◽  
Male Mice ◽  
Intact Male ◽  
Female Mice ◽  
End Organ Damage ◽  
Induced Hypertension ◽  
Post Menopausal

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.

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