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

Hypertension ◽  
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.

Abstract 7: AntagomiR-762 Prevents and Reverses Angiotensin II Induced Aortic Stiffening

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Aortic Stiffness ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
End Organ Damage ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the aortic adventitia. This leads to aortic stiffening, eventually leading to end-organ damage. Through a screen of microRNAs (miRNAs) in the aorta, 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 Ang II-infused mice compared to 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 influence the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, antagomiR-762 administration in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with Ang II for 4 weeks (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + antagomiR-762(last two weeks) [20±1.76 kPa], p<0.0001). Further studies showed that antagomiR-762 reduced mRNA for several collagens and fibronectin and dramatically upregulated collagenases MMP1a, 8 and 13 (Table). Hence, miR-762 plays a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. AntagomiR-762 might represent a new approach to prevent and possibly reverse aortic stiffening and its consequent end-organ damage.

Abstract P231: Inhibition of Mir-762 Prevents and Reverses Ang II Induced Aortic Stiffening

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Aortic Stiffness ◽  
Fold Increase ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

Abstract MP01: Deacetylation Of Mitochondrial Cyclophilin D K166 Inhibits Cytokine-induced Oxidative Stress And Attenuates Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sergey I Dikalov ◽  
Vladimir Mayorov ◽  
Daniel Fehrenbach ◽  
Mingfang Ao ◽  
Alexander Panov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Vascular Function ◽  
Organ Damage ◽  
Cyclophilin D ◽  
Wild Type ◽  
End Organ Damage ◽  
Mitochondrial Superoxide ◽  
Vascular Oxidative Stress

We have previously reported that depletion Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension, however, specific regulation of CypD in hypertension is not clear. Analysis of human arterioles from hypertensive patients did not reveal alterations in CypD levels but showed 3-fold increase in CypD acetylation. We hypothesized that CypD-K166 acetylation promotes vascular oxidative stress and hypertension, and measures to reduce CypD acetylation can improve vascular function and reduce hypertension. Essential hypertension and animal models of hypertension are linked to inactivation of mitochondrial deacetylase Sirt3 by highly reactive lipid oxidation products, isolevuglandins (isoLGs), and supplementation of mice with mitochondria targeted scavenger of isoLGs, mito2HOBA, improves CypD deacetylation. To test the specific role of CypD-K166 acetylation, we developed CypD-K166R deacetylation mimic mutant mice. Mitochondrial respiration, vascular function and systolic blood pressure in CypD-K166R mice was similar to wild-type C57Bl/6J mice. Meanwhile, angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type mice (161 mmHg). Angiotensin II infusion in wild-type mice significantly increased mitochondrial superoxide, impaired endothelial dependent relaxation, and reduced the level of endothelial nitric oxide which was prevented in angiotensin II-infused CypD-K166R mice. Hypertension is linked to increased levels of inflammatory cytokines TNFα and IL-17A promoting vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type aortas which was abrogated in CypD-K166R mice. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We propose that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.

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 Vascular Stiffening Mediated by Rho‐Associated Coiled‐Coil Containing Kinase Isoforms

2021 ◽  
Author(s):  
Yuxin Li ◽  
Haw‐Chih Tai ◽  
Nikola Sladojevic ◽  
Hyung‐Hwan Kim ◽  
James K. Liao
Keyword(s):  
Angiotensin Ii ◽  
Methyl Ester ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Coiled Coil ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Vascular Stiffening ◽  
Aortic Stiffening

Background The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. Methods and Results Hemizygous Rock mice ( Rock1 +/− and Rock2 +/− ) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of Rock1 +/− and Rock2 +/− mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N ω ‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male Rock1 +/− and Rock2 +/− mice. Similar to advancing age, angiotensin II/L‐N ω ‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2 +/− , and to a lesser extent, Rock1 +/− mice. The reduction of aortic stiffening in Rock2 +/− mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in Rock2 −/− mouse embryonic fibroblasts. Conclusions These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.

Abstract 139: Loss of Thymosin b4 Exacerbates Renal and Cardiac Damage in Angiotensin-II Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Nitin Kumar ◽  
Tang-Dong Liao ◽  
Cesar Romero ◽  
Mani Maheshwari ◽  
Ed Peterson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tissue Damage ◽  
Cardiac Fibrosis ◽  
Organ Damage ◽  
Protective Role ◽  
High Expression ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Filtration Barrier

Angiotensin-II (Ang-II)-induced hypertension is associated with tissue damage and fibrosis in the kidney and heart. Thymosin β4 (Tβ4) regulates cell morphology, inflammation and fibrosis in several organs and administration of exogenous Tβ4 is protective in diabetic nephropathy and unilateral ureteral obstruction model. However, role of endogenous Tβ4 in hypertension-induced organ damage is unknown. We hypothesize that, loss of Tβ4 accelerates renal and cardiac fibrosis and damage in Ang-II hypertension. To test our hypothesis, Tβ4 knockout (Tβ4 -/- ) and wild-type (Tβ4 +/+ ) C57BL/6 mice (n=6-10) were infused continuously for six-weeks with either Ang-II (980 ng/kg/min) or vehicle via osmotic minipumps. All the results are presented in table 1. In Ang-II infusion, systolic blood-pressure were not different between both strains (Table 1). Interestingly, urinary albuminuria was significantly higher in Tβ4 -/- mice compared to Tβ4 +/+ mice by Ang-II. High expression of Tβ4 is found in the glomeruli along with high expression of Nephrin, an important protein in the filtration barrier of the kidney. In Ang-II infusion, nephrin protein expression was greatly reduced in mice deficient of Tβ4, suggesting that loss of nephrin is one of the mechanism for elevated urinary albumin in Tβ4 -/- mice. Additionally, renal fibrosis was higher in Tβ4 -/- mice. We also studied cardiac damage and observed that in Ang-II infusion, cardiac hypertrophy and cardiac fibrosis were much higher in Tβ4 -/- mice. These data indicate that loss of endogenous Tβ4 caused significant tissue damage in the kidney and heart in Ang-II hypertension, suggesting renal and cardiac protective role of this peptide.

scholarly journals The deleterious role of the prostaglandin E2 EP3 receptor in angiotensin II hypertension

2020 ◽  
Vol 318 (4) ◽  
pp. H867-H882 ◽  
Author(s):  
Timothy D. Bryson ◽  
Teja S. Pandrangi ◽  
Safa Z. Khan ◽  
Jiang Xu ◽  
Tengis S. Pavlov ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Antihypertensive Drugs ◽  
Cardiac Contractility ◽  
Organ Damage ◽  
Prostaglandin E ◽  
Ang Ii ◽  
End Organ Damage ◽  
Ep3 Receptor

Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E2 (PGE2) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP3 receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP4 receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP3 and EP4 receptors is a major determinant of end-organ damage in the diseased heart. Thus EP3 is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP3 receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP3 receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP3 receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP3-transgenic mice, which overexpress EP3 in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP3 exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP3 receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN. NEW & NOTEWORTHY This study is the first to show that systemic treatment with an EP3 receptor antagonist (L798,106) attenuates the angiotensin II-induced increase in blood pressure in mice. The results from this project could complement existing hypertension therapies by combining blockade of the EP3 receptor with antihypertensive drugs.

Abstract 097: EGF Receptor And ER Stress Mediate End-organ Damage But Not Hypertension Induced By Angiotensin II In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Katherine J Elliott ◽  
Toshiyuki Tsuji ◽  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Steven Forrester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Egf Receptor ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Egfr Activation ◽  
And Oxidative Stress

In cultured vascular smooth muscle cells (VSMC), a metalloprotease ADAM17-dependent EGF receptor (EGFR) activation mediates ERK1/2 activation and subsequent hypertrophy induced by angiotensin II (Ang II). Both ER and oxidative stress are implicated in hypertensive end-organ damage. We hypothesized that pharmacological inhibition of EGFR may prevent end-organ damage but not hypertension in mice infused with Ang II via suppression of ER/oxidative stress. To test this hypothesis, we have evaluated Ang II-induced end-organ damage as well as hypertension in C57Bl/6 mice with or without an EGFR inhibitor erlotinib (20mg/kg/day ip) or ER stress inhibitor 4-phenyl butyric acid (PBA: 1g/kg/day in drinking water). Upon Ang II infusion (1000 ng/kg/min) for 2 weeks, control mice showed phenotypes of cardiac hypertrophy including increased HW/BW ratio (mg/g: 7.9±0.7 vs 5.7±0.6 p<0.01 n=8) and increased LVPWd assessed by cardiac echo (mm: 0.98±0.14 vs 0.69±0.05, p<0.05 n=8) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, cardiac hypertrophy and vascular remodeling were attenuated in mice with Ang II plus erlotinib or PBA; HW/BW ratio (6.8±0.6 or 6.2±0.6 n=8), and cardiac echo (LVPWd: 0.65±0.07 or 0.80±0.07 n=8) compared with saline infusion. Renal fibrosis observed with Ang II infusion was also attenuated in mice with Ang II plus erotinib or PBA. However, Ang II induced similar levels of hypertension in non-treated, erlotinib-treated or PBA-treated mice assessed by telemetry (MAP mmHg: 144±9 vs 149±20 or 139±4). Ang II infusion in mice enhanced ADAM17 and phospho-Tyr EGFR staining in vasculatures of heart and kidney, whereas mice with Ang II plus erlotinib or PBA had diminished phospho-Tyr EGFR staining and no ADAM17 staining in the vasculatures. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused mice with erlotinib or PBA. These data suggest that EGFR activation and subsequent ER stress enhancement are critical for end organ damage via induction of ADAM17 and oxidative stress and is independent from blood pressure regulation.

scholarly journals The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

2016 ◽  
Vol 310 (11) ◽  
pp. F1356-F1365 ◽  
Author(s):  
Sebastian Weiss ◽  
Alva Rosendahl ◽  
Daniel Czesla ◽  
Catherine Meyer-Schwesinger ◽  
Rolf A. K. Stahl ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Organ Damage ◽  
Innate Immune ◽  
Ang Ii ◽  
End Organ Damage ◽  
Induced Hypertension ◽  
Infiltrating Cells ◽  
Deficient Mice

Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g−1·min−1) and salt in wild-type ( n = 34) and C5aR1-deficient mice ( n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.

scholarly journals Class switching and high-affinity immunoglobulin G production by B cells is dispensable for the development of hypertension in mice

2020 ◽  
Author(s):  
Yuhan Chen ◽  
Bethany L Dale ◽  
Matthew R Alexander ◽  
Liang Xiao ◽  
Mingfang Ao ◽  
...  
Keyword(s):  
B Cells ◽  
Immunoglobulin G ◽  
Elevated Serum ◽  
Organ Damage ◽  
Causal Role ◽  
Ang Ii ◽  
End Organ Damage ◽  
High Affinity ◽  
Serum Immunoglobulins

Abstract Aims  Elevated serum immunoglobulins have been associated with experimental and human hypertension for decades but whether immunoglobulins and B cells play a causal role in hypertension pathology is unclear. In this study, we sought to determine the role of B cells and high-affinity class-switched immunoglobulins on hypertension and hypertensive end-organ damage to determine if they might represent viable therapeutic targets for this disease. Methods and results  We purified serum immunoglobulin G (IgG) from mice exposed to vehicle or angiotensin (Ang) II to induce hypertension and adoptively transferred these to wild type (WT) recipient mice receiving a subpressor dose of Ang II. We found that transfer of IgG from hypertensive animals does not affect blood pressure, endothelial function, renal inflammation, albuminuria, or T cell-derived cytokine production compared with transfer of IgG from vehicle infused animals. As an alternative approach to investigate the role of high-affinity, class-switched immunoglobulins, we studied mice with genetic deletion of activation-induced deaminase (Aicda−/−). These mice have elevated levels of IgM but virtual absence of class-switched immunoglobulins such as IgG subclasses and IgA. Neither male nor female Aicda−/− mice were protected from Ang II-induced hypertension and renal/vascular damage. To determine if IgM or non-immunoglobulin-dependent innate functions of B cells play a role in hypertension, we studied mice with severe global B-cell deficiency due to deletion of the membrane exon of the IgM heavy chain (µMT−/−). µMT−/− mice were also not protected from hypertension or end-organ damage induced by Ang II infusion or deoxycorticosterone acetate-salt treatment. Conclusions  These results suggest that B cells and serum immunoglobulins do not play a causal role in hypertension pathology.

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