Unravelling the Lesser Known Facets of Angiotensin II Type 1 Receptor
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Purpose of Review
Hypertension is an important risk factor in various pathologies. Despite enormous advancements in health sciences, the number of hypertensive individuals is increasing worldwide. The complex interplay between genetic and epigenetic factors seems to be a promising pathway to exploring the pathophysiology of hypertension.
Various single gene and genome wide association studies have generated huge but non-reproducible data that highlights the role of some additional but as yet unidentified factor(s) in disease outcome. Dietary pattern and epigenetic mechanism (mainly DNA methylation) have shown a profound effect on blood pressure regulation. Angiotensin II and its receptors are known to play an important role in maintaining blood pressure; hence, a larger section of antihypertensive drugs targets the renin–angiotensin system (RAS). Angiotensin II type 1 receptor (AT1R), besides maintaining blood pressure, also has a role in cancer progression.
Besides other pathways, RAS still remains the main player in blood pressure regulation. Additionally, AT1R has recently emerged as a molecule with diverse roles ranging from physiologic to cancer progression.
KeywordsHypertension Angiotensin receptor blockers Epigenetic Dietary pattern
The authors are thankful to the institute for providing all the infrastructure and required permissions to carry out this work at Department cum National Centre for Human Genome Studies and Research (NCHGSR). A financial grant in the form of DBT fellowship (DBT-JRF) by the Department of Biotechnology, Ministry of Science and Technology, Government of India, to Mayank Chaudhary is also thankfully acknowledged.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflicts of interest.
Human and Animal Rights and Informed Consent
None of the authors performed any studies on human or animal subjects for this review article.
Papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance
- 4.• Shamieh SE, Siest VS. Genetic biomarkers of hypertension and future challenges integrating epigenomics. Clin Chim Acta. 2012;414:259–65. doi: 10.1016/j.cca.2012.09.018. This review highlights candidate genes of metabolic pathways other than RAS involved in blood pressure regulation CrossRefPubMedGoogle Scholar
- 6.• Cuddy MLS. Treatment of hypertension: guidelines from JNC 7 (Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure). J Prac Nurs. 2005;55(4):17–23. This is JNC VII report having complete description about diagnosis, detection and treatment of high blood pressure Google Scholar
- 8.• Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology. 2003;144(6):2179–83. doi: 10.1210/en.2003-0150. This mini review describes the importance of paracrine (tissue RAS) in addition to the conventional endocrine RAS. Paper also includes detail of transgenic animal models of tissue RAS CrossRefPubMedGoogle Scholar
- 25.• Elton TS, Martin MM. Alternative splicing: a novel mechanism to fine tune the expression and function of the human AT1 receptor. Trends Endocrinol Metabol. 2003;14(2):66–71. doi: 10.1016/S1043-2760(02)00038-3. This article details about different transcript(s) formation through alternate splicing and their functional significance CrossRefGoogle Scholar
- 27.•• Zhang H, Unal H, Gati C, Han GW, Liu W, Zatsepin NA, et al. Structure of the angiotensin receptor revealed by serial femtosecond crystallography. Cell. 2015;161(4):833–44. doi: 10.1016/j.cell.2015.04.011. This paper is the first to report details of crystal structure of human AT1R in complex with selective antagonist CrossRefPubMedPubMedCentralGoogle Scholar
- 28.•• Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, et al. Structural basis for ligand recognition and functional selectivity at angiotensin receptor. J Biol Chem. 2015;290(49):29127–39. doi: 10.1074/jbc.M115.689000. This article is further extension of work on crystal structure of AT1R highlighting role of specific amino acid residues of AT1R on its peptide binding efficiency CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Wei J, Yan L, Hui SH, Lin J, Yun SY, Qi H, et al. Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin. 2003;24(11):1083–8.Google Scholar
- 33.Su SL, Lu KC, Lin YF, Hsu YJ, Lee PY, Yang HY, et al. Gene polymorphisms of angiotensin converting enzyme and angiotensin II type 1 receptor among chronic kidney disease patients in Chinese population. J Renin-Angiotensin-Aldosterone Syst. 2012;13(1):148–54. doi: 10.1177/1470320311430989.CrossRefPubMedGoogle Scholar
- 35.Patnaik M, Pati P, Swain SN, Mohapatra MK, Dwibedi B, Kar SK, et al. Aldosterone synthase C-344 T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha. India J Genet. 2014;93(3):799–808.CrossRefPubMedGoogle Scholar
- 37.Smilde TD, Zuurman MW, Hillege HL, Veldhuisen DJ, Gilst WH, Steege G, et al. Renal function dependent association of AGTR1 polymorphism (A1166C) and electrocardiographic left-ventricular hypertrophy. Am J Hypertens. 2007;20(10):1097–103. doi: 10.1016/j.amjhyper.2007.04.023.CrossRefPubMedGoogle Scholar
- 39.Shah VN, Cheema BS, Sharma R, Khullar M, Kohli HS, Ahluwali TS, et al. ACAC beta gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. Mol Cell Biochem. 2013;372(1–2):191–8. doi: 10.1007/s11010-012-1460-2.CrossRefPubMedGoogle Scholar
- 40.Jones GT, Thompson AR, Bockxmeer FM, Hafez H, Cooper JA, Golledge J, et al. Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts. Arterioscler Thromb Vasc Biol. 2008;28(4):764–70. doi: 10.1161/ATVBAHA.107.155564.CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Kaczmarczyk M, Kuprjanowicz A, Loniewska B, Goracy I, Taryma LO, Skonieczna ZK, et al. Epistatic interaction between common AGT G(-6)A (rs5051) and AGTR1 A1166C (rs5186) variants contributes to variation in kidney size at birth. Gene. 2015;572(1):72–8. doi: 10.1016/j.gene.2015.06.071.CrossRefPubMedGoogle Scholar
- 51.Campbell CY, Fang BF, Guo X, Peralta CA, Psaty BM, Rich SS, et al. Association between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the multi-ethnic study of atherosclerosis. Am J Nephrol. 2010;32(2):156–62. doi: 10.1159/000315866.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Zain SM, Mohamed Z, Mahadeva S, Rampal S, Basu RC, Cheah PL, et al. Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population. PLoS One. 2013;8(3):e58538. doi: 10.1371/journal.pone.0058538.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.Srivastava S, Bhagi S, Kumari B, Chandra K, Sarkar S, Ashraf MZ. Association of polymorphisms in angiotensin and aldosterone synthase genes of the renin-angiotensin-aldosterone system with high-altitude pulmonary edema. J Renin-Angiotensin-Aldosterone Syst. 2012;13(1):155–60. doi: 10.1177/1470320311430990.CrossRefPubMedGoogle Scholar
- 62.Koehle MS, Wang P, Guenette JA, Rupert JL. No association between variants in the ACE and angiotensin II type 1 receptor genes and acute mountain sickness in Nepalese pilgrims to the Janai Purnima Festival at 4380 m. High Alt Med Biol. 2006;7(4):281–9. doi: 10.1089/ham.2006.7.281.CrossRefPubMedGoogle Scholar
- 66.Chandra S, Narang R, Sreenivas V, Bhatia J, Saluja D, Srivastava K. Association of angiotensin II type 1 receptor (A1166C) gene polymorphism and its increased expression in essential hypertension: a case-control study. PLoS One. 2014;9(7):e101502. doi: 10.1371/journal.pone.0101502.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.Singh DK, Jajodia A, Kaur H, Kukreti R, Karthikeyan M. Gender specific association of RAS gene polymorphism with essential hypertension: a case-control study. Biomed Res Int. 2014;538053 doi: 10.1155/2014/538053.
- 69.• Choi SW, Friso S. Epigenetics: a new bridge between nutrition and health. Adv Nutr. 2010;1(1):8–16. doi: 10.3945/an.110.1004. This review article describes the effect of nutrients (e.g., folate) and bioactive food components (e.g., tea polyphenols, isothiocynates) on DNA methylation. Paper also describes various epigenetic mechanisms in addition to nucleosome and chromatin structure CrossRefPubMedPubMedCentralGoogle Scholar
- 71.•• 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. doi: 10.1371/journal.pone.0108161. The paper provides experimental evidence of novel mechanism of selectively altered methylation of specific CpG at AT1R/AT2R in the developing vasculature and resultant increase in vascular contractility caused by perinatal nicotine exposure CrossRefPubMedPubMedCentralGoogle Scholar
- 74.•• Riviere G, Lienhard G, 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. This article examines role of epigenetic mechanisms on the control of somatic ACE expression both in vitro and in vivo. Methodology involving bisulphite sequencing, RT-qPCR and well-designed strategy was able to indicate strong influence of such mechanisms on ACE expression CrossRefPubMedGoogle Scholar
- 76.Smolarek I, Wyszko E, Barciszewska AM, Nowak S, Gawronska I, Jablecka A, et al. Global DNA methylation changes in blood of patients with essential hypertension. Med Sci Monit. 2010;16(3):149–55.Google Scholar
- 82.•• Fan R, Mao S, Zhong F, Gong M, Yin F, Hao L, 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. doi: 10.1159/000442366. This is the first paper to investigate correlation of AT1R methylation with risk of EH in humans. Article also includes correlation between methylation and other clinical indicators CrossRefPubMedGoogle Scholar
- 83.Azevedo H, Fujita A, Bando SY, Lamashita P, Filho MCA. Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression. PLoS One. 2014;9(11):e110934. doi: 10.1371/journal.pone.0110934.CrossRefPubMedPubMedCentralGoogle Scholar
- 88.Salata C, Machado SCF, Mencalha AL, Andrade CB, Campos VM, Lacerda MCA, et al. Chemotherapy and radiation regimes to breast cancer treatment induce changes in mRNA levels of renin-angiotensin system related genes in cardiac tissue. J Renin-Angiotensin-Aldosterone Syst. 2012;14(4):330–6.CrossRefPubMedGoogle Scholar