Login Register Cart 0
Generic placeholder image

Current Hypertension Reviews

Editor-in-Chief

ISSN (Print): 1573-4021
ISSN (Online): 1875-6506

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Anti-Hypertensive Potential and Epigenetics of Angiotensin II type 2 Receptor (AT2R)

Author(s): Mayank Chaudhary*

Volume 17, Issue 3, 2021

Published on: 09 December, 2020

Page: [176 - 180] Pages: 5

DOI: 10.2174/1573402116999201209203015

Price: $65

Abstract

Background: Renin angiotensin system (RAS) is a critical pathway involved in blood pressure regulation. Octapeptide, angiotensin II (Ang II), is a biologically active compound of RAS pathway which mediates its action by binding to either angiotensin II type 1 receptor (AT1R) or angiotensin II type 2 receptor (AT2R). Binding of Ang II to AT1R facilitates blood pressure regulation, whereas AT2R is primarily involved in wound healing and tissue remodeling.

Objectives: Recent studies have highlighted the additional role of AT2R to counterbalance the detrimental effects of AT1R. Activation of angiotensin II type 2 receptor using AT2R agonist has shown the effect on natriuresis and release of nitric oxide. Additionally, AT2R activation has been found to inhibit angiotensin converting enzyme (ACE) and enhance angiotensin receptor blocker (ARB) activity. These findings highlight the potential of AT2R as a novel therapeutic target against hypertension.

Conclusion: The potential role of AT2R highlights the importance of exploring additional mechanisms that might be crucial for AT2R expression. Epigenetic mechanisms, including DNA methylation and histone modification, have been explored vastly with relation to cancer, but the role of such mechanisms in the expression of AT2R has recently gained interest.

Keywords: Epigenetics, DNA methylation, hypertension, angiotensin II type 2 receptor, blood pressure regulation.

« Previous Next »
Graphical Abstract

[1]
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365(9455): 217-23.
[http://dx.doi.org/10.1016/S0140-6736(05)17741-1] [PMID: 15652604]
[2]
Simonetti GD, Mohaupt MG, Bianchetti MG. Monogenic forms of hypertension. Eur J Pediatr 2012; 171(10): 1433-9.
[http://dx.doi.org/10.1007/s00431-011-1440-7] [PMID: 21404100]
[3]
Unger T, Borghi C, Charchar F, et al. 2020 International society of hypertension global hypertension practice guidelines. Hypertension 2020; 75(6): 1334-57.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15026] [PMID: 32370572]
[4]
El Shamieh S, Visvikis-Siest S. Genetic biomarkers of hypertension and future challenges integrating epigenomics. Clin Chim Acta 2012; 414: 259-65.
[http://dx.doi.org/10.1016/j.cca.2012.09.018] [PMID: 23010416]
[5]
Cuddy MLS. Treatment of hypertension: guidelines from JNC 7 (the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 1). J Pract Nurs 2005; 55(4): 17-21.
[PMID: 16512265]
[6]
Kario K, Morisawa Y, Sukonthasarn A, et al. Hypertension Cardiovascular Outcome Prevention, Evidence in Asia (HOPE Asia) Network. COVID-19 and hypertension-evidence and practical management: Guidance from the HOPE Asia Network. J Clin Hypertens (Greenwich) 2020; 00: 1-11.
[http://dx.doi.org/10.1111/jch.13917] [PMID: 32643874]
[7]
Shibata S, Arima H, Asayama K, et al. Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of Hypertension Task Force on COVID-19. Hypertens Res 2020; 43(10): 1028-46.
[http://dx.doi.org/10.1038/s41440-020-0515-0] [PMID: 32737423]
[8]
South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol 2020; 16(6): 305-7.
[http://dx.doi.org/10.1038/s41581-020-0279-4] [PMID: 32246101]
[9]
Dinh DT, Frauman AG, Johnston CI, Fabiani ME. Angiotensin receptors: distribution, signalling and function. Clin Sci (Lond) 2001; 100(5): 481-92.
[http://dx.doi.org/10.1042/cs1000481] [PMID: 11294688]
[10]
Azushima K, Morisawa N, Tamura K, Nishiyama A. Recent research advances in renin-angiotensin-aldosterone system receptors. Curr Hypertens Rep 2020; 22(3): 22.
[http://dx.doi.org/10.1007/s11906-020-1028-6] [PMID: 32114685]
[11]
Chow BSM, Allen TJ. Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease. Clin Sci (Lond) 2016; 130(15): 1307-26.
[http://dx.doi.org/10.1042/CS20160243] [PMID: 27358027]
[12]
Carey RM. AT2 receptors: Potential therapeutic targets for hypertension. Am J Hypertens 2017; 30(4): 339-47.
[PMID: 27664954]
[13]
Carey RM. Update on angiotensin AT2 receptors. Curr Opin Nephrol Hypertens 2017; 26(2): 91-6.
[PMID: 27906747]
[14]
Kaschina E, Namsolleck P, Unger T. AT2 receptors in cardiovascular and renal diseases. Pharmacol Res 2017; 125(Pt A): 39-47.
[http://dx.doi.org/10.1016/j.phrs.2017.07.008] [PMID: 28694144]
[15]
Sumners C, de Kloet AD, Krause EG, Unger T, Steckelings UM. Angiotensin type 2 receptors: blood pressure regulation and end organ damage. Curr Opin Pharmacol 2015; 21: 115-21.
[http://dx.doi.org/10.1016/j.coph.2015.01.004] [PMID: 25677800]
[16]
Widdop RE, Jones ES, Hannan RE, Gaspari TA. Angiotensin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol 2003; 140(5): 809-24.
[http://dx.doi.org/10.1038/sj.bjp.0705448] [PMID: 14530223]
[17]
Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther 2008; 120(3): 292-316.
[http://dx.doi.org/10.1016/j.pharmthera.2008.08.009] [PMID: 18804122]
[18]
Hannan RE, Davis EA, Widdop RE. Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide. Br J Pharmacol 2003; 140(5): 987-95.
[http://dx.doi.org/10.1038/sj.bjp.0705484] [PMID: 14530222]
[19]
Ichiki T, Labosky PA, Shiota C, et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 1995; 377(6551): 748-50.
[http://dx.doi.org/10.1038/377748a0] [PMID: 7477267]
[20]
Dao VT, Medini S, Bisha M, et al. Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors. Biochem Pharmacol 2016; 112: 24-36.
[http://dx.doi.org/10.1016/j.bcp.2016.05.011] [PMID: 27235748]
[21]
Naito T, Ma LJ, Yang H, et al. Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis. Am J Physiol Renal Physiol 2010; 298(3): F683-91.
[http://dx.doi.org/10.1152/ajprenal.00503.2009] [PMID: 20042458]
[22]
Padia SH, Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pflugers Arch 2013; 465(1): 99-110.
[http://dx.doi.org/10.1007/s00424-012-1146-3] [PMID: 22949090]
[23]
Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA 1999; 96(11): 6506-10.
[http://dx.doi.org/10.1073/pnas.96.11.6506] [PMID: 10339618]
[24]
Kemp BA, Howell NL, Gildea JJ, Keller SR, Padia SH, Carey RM. AT₂ receptor activation induces natriuresis and lowers blood pressure. Circ Res 2014; 115(3): 388-99.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.304110] [PMID: 24903104]
[25]
Peluso AAB, Santos RAS, Unger T, Steckelings UM. The angiotensin type 2 receptor and the kidney. Curr Opin Nephrol Hypertens 2017; 26(1): 36-42.
[http://dx.doi.org/10.1097/MNH.0000000000000289] [PMID: 27798458]
[26]
Brouwers S, Smolders I, Wainford RD, Dupont AG. Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats. Clin Sci (Lond) 2015; 129(1): 81-92.
[http://dx.doi.org/10.1042/CS20140776] [PMID: 25655919]
[27]
de Kloet AD, Steckelings UM, Sumners C. Protective angiotensin type 2 receptors in the brain and hypertension. Curr Hypertens Rep 2017; 19(6): 46.
[http://dx.doi.org/10.1007/s11906-017-0746-x] [PMID: 28488048]
[28]
Li Z, Iwai M, Wu L, et al. Role of AT2 receptor in the brain in regulation of blood pressure and water intake. Am J Physiol Heart Circ Physiol 2003; 284(1): H116-21.
[http://dx.doi.org/10.1152/ajpheart.00515.2002] [PMID: 12388241]
[29]
Gao J, Zhang H, Le KD, Chao J, Gao L. Activation of central angiotensin type 2 receptors suppresses norepinephrine excretion and blood pressure in conscious rats. Am J Hypertens 2011; 24(6): 724-30.
[http://dx.doi.org/10.1038/ajh.2011.33] [PMID: 21394088]
[30]
Kemp BA, Howell NL, Keller SR, Gildea JJ, Padia SH, Carey RM. AT2 receptor activation prevents sodium retention and reduces blood pressure in angiotensin II dependent hypertension. Circ Res 2016; 119(4): 532-43.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308384] [PMID: 27323774]
[31]
Renziehausen A, Wang H, Rao B, et al. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene 2019; 38(13): 2320-36.
[http://dx.doi.org/10.1038/s41388-018-0563-y] [PMID: 30478450]
[32]
Liang M. Epigenetic mechanisms and Hypertension. Hypertension 2018; 72(6): 1244-54.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11171] [PMID: 30571238]
[33]
Stoll S, Wang C, Qiu H. DNA methylation and histone modification in hypertension. Int J Mol Sci 2018; 19(4): 1174.
[http://dx.doi.org/10.3390/ijms19041174] [PMID: 29649151]
[34]
Bogdarina I, Welham S, King PJ, Burns SP, Clark AJL. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ Res 2007; 100(4): 520-6.
[http://dx.doi.org/10.1161/01.RES.0000258855.60637.58] [PMID: 17255528]
[35]
Xiao D, Dasgupta C, Li Y, Huang X, Zhang L. Perinatal nicotine exposure increases angiotensin II receptor-mediated vascular contractility in adult offspring. PLoS One 2014; 9(9): e108161.
[http://dx.doi.org/10.1371/journal.pone.0108161] [PMID: 25265052]
[36]
Smolarek I, Wyszko E, Barciszewska AM, et al. Global DNA methylation changes in blood of patients with essential hypertension. Med Sci Monit 2010; 16(3): CR149-55.
[PMID: 20190686]
[37]
Kulkarni A, Chavan-Gautam P, Mehendale S, Yadav H, Joshi S. Global DNA methylation patterns in placenta and its association with maternal hypertension in pre-eclampsia. DNA Cell Biol 2011; 30(2): 79-84.
[http://dx.doi.org/10.1089/dna.2010.1084] [PMID: 21043832]
[38]
Wang X, Falkner B, Zhu H, et al. A genome-wide methylation study on essential hypertension in young African American males. PLoS One 2013; 8(1): e53938.
[http://dx.doi.org/10.1371/journal.pone.0053938] [PMID: 23325143]
[39]
Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM. Epigenetic regulation of 11 β-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest 2004; 114(8): 1146-57.
[http://dx.doi.org/10.1172/JCI21647] [PMID: 15489962]
[40]
Zhang LN, Liu PP, Wang L, et al. Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLoS One 2013; 8(5): e63455.
[http://dx.doi.org/10.1371/journal.pone.0063455] [PMID: 23691048]
[41]
Rivière G, Lienhard D, Andrieu T, Vieau D, Frey BM, Frey FJ. Epigenetic regulation of somatic angiotensin-converting enzyme by DNA methylation and histone acetylation. Epigenetics 2011; 6(4): 478-89.
[http://dx.doi.org/10.4161/epi.6.4.14961] [PMID: 21364323]
[42]
Fan R, Mao S, Zhong F, et al. Association of AGTR1 promoter methylation levels with essential hypertension risk: A matched case-control study. Cytogenet Genome Res 2015; 147(2-3): 95-102.
[http://dx.doi.org/10.1159/000442366] [PMID: 26658476]
[43]
Chaudhary M, Chaudhary S. Functional relevance of promoter CpG island of human Angiotensin II type 1 receptor (AT1R) gene. Mol Cell Biochem 2019; 457(1-2): 31-40.
[http://dx.doi.org/10.1007/s11010-019-03509-8] [PMID: 30790131]
[44]
Li Y, Xiao D, Dasgupta C, et al. Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of angiotensin II receptors. Stroke 2012; 43(9): 2483-90.
[http://dx.doi.org/10.1161/STROKEAHA.112.664698] [PMID: 22738920]
[45]
Li Y, Xiao D, Yang S, Zhang L. Promoter methylation represses AT2R gene and increases brain hypoxic-ischemic injury in neonatal rats. Neurobiol Dis 2013; 60: 32-8.
[http://dx.doi.org/10.1016/j.nbd.2013.08.011] [PMID: 23978469]
[46]
Mesquita FF, Gontijo JAR, Boer PA. Maternal undernutrition and the offspring kidney: from fetal to adult life. Braz J Med Biol Res 2010; 43(11): 1010-8.
[http://dx.doi.org/10.1590/S0100-879X2010007500113] [PMID: 21049242]
[47]
Goyal R, Goyal D, Leitzke A, Gheorghe CP, Longo LD. Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod Sci 2010; 17(3): 227-38.
[http://dx.doi.org/10.1177/1933719109351935] [PMID: 19923380]
[48]
Zhao Y, Zhu Q, Sun S, et al. Renal transplantation increases angiotensin II receptor-mediated vascular contractility associated with changes of epigenetic mechanisms. Int J Mol Med 2018; 41(4): 2375-88.
[http://dx.doi.org/10.3892/ijmm.2018.3435] [PMID: 29393347]
[49]
Pandey A, Goru SK, Kadakol A, Malek V, Sharma N, Gaikwad AB. H2AK119 monoubiquitination regulates Angiotensin II receptor mediated macrophage infiltration and renal fibrosis in type 2 diabetic rats. Biochimie 2016; 131: 68-76.
[http://dx.doi.org/10.1016/j.biochi.2016.09.016] [PMID: 27693081]
[50]
Pandey A, Gaikwad AB. Compound 21 and Telmisartan combination mitigates type 2 diabetic nephropathy through amelioration of caspase mediated apoptosis. Biochem Biophys Res Commun 2017; 487(4): 827-33.
[http://dx.doi.org/10.1016/j.bbrc.2017.04.134] [PMID: 28456626]
[51]
Li B, Zhu Y, Chen H, et al. Decreased H3K9ac level of AT2R mediates the developmental origin of glomerulosclerosis induced by prenatal dexamethasone exposure in male offspring rats. Toxicology 2019; 411: 32-42.
[http://dx.doi.org/10.1016/j.tox.2018.10.013] [PMID: 30359671]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy