Cytosolic Phospholipase A2α Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-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.

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

Hypertension ◽

10.1161/hyp.68.suppl_1.p135 ◽

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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Group IV Cytosolic Phospholipase A2α Is Critical for the Development of Angiotensin II-Induced Hypertension and Associated Pathogenesis

10.21007/etd.cghs.2014.0160 ◽

2014 ◽

Author(s):

Nayaab Khan

Keyword(s):

Angiotensin Ii ◽

Group Iv ◽

Cytosolic Phospholipase ◽

Induced Hypertension ◽

Cytosolic Phospholipase A2α

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Brain Cytosolic Phospholipase A2α Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice

American Journal of Hypertension ◽

10.1093/ajh/hpy009 ◽

2018 ◽

Vol 31 (5) ◽

pp. 622-629 ◽

Cited By ~ 5

Author(s):

Chi Young Song ◽

Nayaab S Khan ◽

Francesca-Fang Liao ◽

Bin Wang ◽

Ji Soo Shin ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Angiotensin Ii ◽

Reactive Oxygen Species Production ◽

Reactive Oxygen ◽

Oxygen Species ◽

Male Mice ◽

Cytosolic Phospholipase ◽

Induced Hypertension ◽

Cytosolic Phospholipase A2α ◽

Species Production

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Cytochrome P450-Dependent Renal Metabolism of Arachidonic Acid in a Rat Model of Angiotensin II induced Hypertension and End-Organ Damage

10.1240/sav_gbm_2002_h_000154 ◽

2002 ◽

Vol 2002 (Fall) ◽

Author(s):

Eva K??rgel ◽

Horst Honeck ◽

Dominik N. M??ller ◽

J??rgen Theuer ◽

Friedrich C. Luft ◽

...

Keyword(s):

Arachidonic Acid ◽

Cytochrome P450 ◽

Angiotensin Ii ◽

Rat Model ◽

Organ Damage ◽

Renal Metabolism ◽

End Organ Damage ◽

Induced Hypertension

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Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2016.12.001 ◽

2017 ◽

Vol 103 ◽

pp. 11-21 ◽

Cited By ~ 17

Author(s):

Mengcheng Shen ◽

Jude Morton ◽

Sandra T Davidge ◽

Zamaneh Kassiri

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Organ Damage ◽

End Organ Damage ◽

Induced Hypertension

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Abstract 070: AntagomiR-762 Prevents Angiotensin II Induced Aortic Fibrosis and Stiffening

Hypertension ◽

10.1161/hyp.66.suppl_1.070 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Kim Ramil C Montaniel ◽

Jing Wu ◽

Matthew R Bersi ◽

Liang Xiao ◽

Hana A Itani ◽

...

Keyword(s):

Angiotensin Ii ◽

Organ Damage ◽

Matrix Proteins ◽

Locked Nucleic Acid ◽

Ang Ii ◽

End Organ Damage ◽

Acid Inhibitor ◽

Vascular Stiffening ◽

Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the vascular adventitia. This causes vascular stiffening, which increases pulse wave velocity and contributes to end-organ damage. Through a screen of vascular microRNAs (miRNAs), we found that miR-762 is the most upregulated miRNA in mice with angiotensin II (Ang II)-induced HTN. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in aortas of Ang II-infused mice compared with controls. This was a direct effect of Ang II, as miR-762 upregulation was not eliminated by lowering blood pressure with hydralazine and hydrochlorothiazide and was increased only 2-fold in DOCA salt HTN. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762 (antagomiR-762). AntagomiR-762 administration did not alter the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic energy storage that occurs in systole (Table). Further studies showed that antagomiR-762 dramatically affected vascular matrix proteins, reducing mRNA for several collagens and fibronectin and dramatically upregulating collagenases MMP1a, 8 and 13 (Table). Thus, miR-762 has a major role in modulating vascular stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation and normalizes aortic stiffness. AntagomiR-762 might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

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