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 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.

scholarly journals Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice

2015 ◽  
Vol 308 (9) ◽  
pp. F981-F992 ◽  
Author(s):  
Brett L. Jennings ◽  
Joseph A. Moore ◽  
Ajeeth K. Pingili ◽  
Anne M. Estes ◽  
Xiao R. Fang ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Renal Dysfunction ◽  
Urine Output ◽  
Organ Damage ◽  
Antioxidant Systems ◽  
Ang Ii ◽  
Female Mice ◽  
Induced Hypertension ◽  
17Β Estradiol ◽  
Cytochrome P 450

Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng·kg−1·min−1) infused by miniosmotic pumps for 2 wk in female Cyp1b1+/+ mice did not alter water consumption, urine output, Na+ excretion, osmolality, or protein excretion. However, in Cyp1b1−/− mice, ANG II infusion significantly increased ( P < 0.05) water intake (5.50 ± 0.42 ml/24 h with vehicle vs. 8.80 ± 0.60 ml/24 h with ANG II), urine output (1.44 ± 0.37 ml/24 h with vehicle vs. 4.30 ± 0.37 ml/24 h with ANG II), and urinary Na+ excretion (0.031 ± 0.016 mmol/24 h with vehicle vs. 0.099 ± 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg with vehicle vs. 1,280 ± 205 mosM/kg with ANG II), and caused proteinuria (2.60 ± 0.30 mg/24 h with vehicle vs. 6.96 ± 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial α-smooth muscle actin, collagen, and transforming growth factor-β in Cyp1b1−/− but not Cyp1b1+/+ mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17β-estradiol metabolite 2-methoxyestradiol in Cyp1b1−/− but not Cyp1b1+/+ mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17β-estradiol.

scholarly journals Cytosolic Phospholipase A2α Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-Induced Hypertension

2015 ◽  
Vol 29 (2) ◽  
pp. 258-265 ◽  
Author(s):  
Nayaab S. Khan ◽  
Chi Young Song ◽  
Shyamala Thirunavukkarasu ◽  
Xiao R. Fang ◽  
Joseph V. Bonventre ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Dysfunction ◽  
Organ Damage ◽  
End Organ Damage ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Cytosolic Phospholipase A2α

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 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 P155: B Cells Are Not Necessary for the Developmentof Ang II-induced Hypertension and End-Organ Damage

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Yuhan Chen ◽  
Bethany L Dale ◽  
Arvind K Pandey ◽  
Matthew R Alexander ◽  
Fanny Laroumanie ◽  
...  
Keyword(s):  
B Cells ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Induced Hypertension

Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension

2017 ◽  
Vol 39 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Xiaojie Li ◽  
Yuhan Lin ◽  
Hongyu Zhou ◽  
Yao Li ◽  
Aimei Wang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Induced Hypertension

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.

scholarly journals Involvement of cytochrome P-450 1B1 in renal dysfunction, injury, and inflammation associated with angiotensin II-induced hypertension in rats

2012 ◽  
Vol 302 (4) ◽  
pp. F408-F420 ◽  
Author(s):  
Brett L. Jennings ◽  
Larry J. Anderson ◽  
Anne M. Estes ◽  
Xiao R. Fang ◽  
Chi Young Song ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
P38 Mapk ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Organ Damage ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Novel Target ◽  
Renal Vascular ◽  
Cytochrome P 450

We investigated the contribution of cytochrome P-450 1B1 (CYP1B1) to renal dysfunction and organ damage associated with ANG II-induced hypertension in rats. ANG II (300 ng·kg−1·min−1) or vehicle were infused for 2 wk, with daily injections of a selective CYP1B1 inhibitor, 2,4,3′,5′-tetramethoxystilbene (TMS; 300 μg/kg ip), or its vehicle. ANG II increased blood pressure and renal CYP1B1 activity that were prevented by TMS. ANG II also increased water intake and urine output, decreased glomerular filtration rate, increased urinary Na+ and K+ excretion, and caused proteinuria, all of which were prevented by TMS. ANG II infusion caused hypertrophy, endothelial dysfunction, and increased reactivity of renal and interlobar arteries to vasoconstrictor agents and renal vascular resistance and interstitial fibrosis as indicated by accumulation of α-smooth muscle actin, fibronectin, and collagen, and inflammation as indicated by increased infiltration of CD-3+ cells; these effects were inhibited by TMS. ANG II infusion also increased production of reactive oxygen species (ROS) and activities of NADPH oxidase, ERK1/2, p38 MAPK, and c-Src that were prevented by TMS. TMS alone had no effect on any of the above parameters. These data suggest that CYP1B1 contributes to the renal pathophysiological changes associated with ANG II-induced hypertension, most likely via increased ROS production and activation of ERK1/2, p38 MAPK, and c-Src and that CYP1B1 could serve as a novel target for treating renal disease associated with hypertension.

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