Molecular and Cellular Biochemistry

, Volume 402, Issue 1–2, pp 1–8 | Cite as

Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development

  • Fang Pei
  • Xinquan Wang
  • Rongchuan Yue
  • Caiyu Chen
  • Ji Huang
  • Jie Huang
  • Xiaohui LiEmail author
  • Chunyu ZengEmail author


Angiotensin type 1a receptor (AT1aR) is thought to play an important role in the development of hypertension. However, it is unknown how the AT1aR expression in vascular tissue is changed during the development of hypertension or if the degree of methylation in the AT1aR promoter correlates with the expression of AT1aR. To address these questions, we measured AT1aR mRNA, protein expression, and methylation status of the AT1aR promoter in the aorta and mesenteric artery of male spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rats acting as controls at pre-hypertensive (4 weeks), evolving (10 weeks), and established (20 weeks) stages of hypertension. The expression of the AT1aR mRNA and protein was not different between the SHRs and WKY rats at 4 weeks. However, they were significantly greater in SHRs than in WKY rats at 20 weeks. Bisulfite sequencing revealed that the AT1aR promoter from the aorta and mesenteric artery of the SHRs was progressively hypo-methylated with age as compared with their WKY rat counterparts. These results suggest that the heightened AT1aR expression in SHRs is related to the AT1aR promoter hypo-methylation, which might be a consequence of the increased blood pressure and may be important in the maintenance of high blood pressure.


Hypertension AT1 receptor DNA methylation Artery SHRs 



This study was supported by grants from the National Natural Science Foundation of China (No. 81200193 and No. 81273507).

Conflict of interest

None declared.


  1. 1.
    Unger T, Paulis L, Sica DA (2011) Therapeutic perspectives in hypertension: novel means for renin-angiotensin-aldosterone system modulation and emerging device-based approaches. Eur Heart J 32(22):2739–2747CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Bader M (2010) Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Annu Rev Pharmacol Toxicol 50:439–465CrossRefPubMedGoogle Scholar
  3. 3.
    Savoia C, Burger D, Nishigaki N et al (2011) Angiotensin II and the vascular phenotype in hypertension. Expert Rev Mol Med 13:e11CrossRefPubMedGoogle Scholar
  4. 4.
    Navar LG, Prieto MC, Satou R et al (2011) Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Curr Opin Pharmacol 11(2):180–186CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Dasgupta C, Zhang L (2011) Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discov Today 16(1–2):22–34CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Aplin M, Bonde MM, Hansen JL (2009) Molecular determinants of angiotensin II type 1 receptor functional selectivity. J Mol Cell Cardiol 46(1):15–24CrossRefPubMedGoogle Scholar
  7. 7.
    Higuchi S, Ohtsu H, Suzuki H et al (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112(8):417–428CrossRefGoogle Scholar
  8. 8.
    Nguyen Dinh Cat A, Touyz RM (2011) Cell signaling of angiotensin II on vascular tone: novel mechanisms. Curr Hypertens Rep 13(2):122–128CrossRefGoogle Scholar
  9. 9.
    Kitami Y, Okura T, Marumoto K et al (1992) Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. Biochem Biophys Res Commun 188(1):446–452CrossRefPubMedGoogle Scholar
  10. 10.
    Llorens-Cortes C, Greenberg B, Huang H et al (1994) Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis. Hypertension 24(5):538–548CrossRefPubMedGoogle Scholar
  11. 11.
    Gasc JM, Shanmugam S, Sibony M et al (1994) Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. Hypertension 24(5):531–537CrossRefPubMedGoogle Scholar
  12. 12.
    Du Y, Guo DF, Inagami T et al (1996) Regulation of ANG II-receptor subtype and its gene expression in adrenal gland. Am J Physiol 271(2 Pt 2):H440–H446PubMedGoogle Scholar
  13. 13.
    Nguyen Dinh Cat A, Montezano AC, Burger D et al (2013) Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 19(10):1110–1120CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Imaizumi S, Miura S, Yahiro E et al (2013) Class- and molecule-specific differential effects of angiotensin II type 1 receptor blockers. Curr Pharm Des 19(17):3002–3008CrossRefPubMedGoogle Scholar
  15. 15.
    Frey FJ (2005) Methylation of CpG islands: potential relevance for hypertension and kidney diseases. Nephrol Dial Transplant 20(5):868–869CrossRefPubMedGoogle Scholar
  16. 16.
    Bogdarina I, Welham S, King PJ et al (2007) Epigenetic modification of the renin- angiotensin system in the fetal programming of hypertension. Circ Res 100(4):520–526CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Friso S, Pizzolo F, Choi SW et al (2008) Epigenetic control of 11 beta- hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis 199(2):323–327CrossRefPubMedGoogle Scholar
  18. 18.
    Smolarek I, Wyszko E, Barciszewska AM et al (2010) Global DNA methylation changes in blood of patients with essential hypertension. Med Sci Monit 16(3):CR149–CR155PubMedGoogle Scholar
  19. 19.
    Cho HM, Lee HA, Kim HY et al (2011) Expression of Na+–K+–2Cl– cotransporter 1 is epigenetically regulated during postnatal development of hypertension. Am J Hypertens 24(12):1286–1293CrossRefPubMedGoogle Scholar
  20. 20.
    Bellavia A, Urch B, Speck M et al (2013) DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments. J Am Heart Assoc 2(3):e000212CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Wang X, Falkner B, Zhu H et al (2013) A genome-wide methylation study on essential hypertension in young African American males. PLoS One 8(1):e53938CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Wang F, Demura M, Cheng Y et al (2014) Dynamic CCAAT/enhancer binding protein-associated changes of DNA methylation in the angiotensinogen gene. Hypertension 63(2):281–288CrossRefPubMedGoogle Scholar
  23. 23.
    Meissner A, Mikkelsen TS, Gu H et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205):766–770PubMedCentralPubMedGoogle Scholar
  24. 24.
    Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13(7):484–492CrossRefPubMedGoogle Scholar
  25. 25.
    Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Maunakea AK, Nagarajan RP, Bilenky M et al (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466(7303):253–257CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408CrossRefPubMedGoogle Scholar
  28. 28.
    Viswanathan M, Tsutsumi K, Correa FM et al (1991) Changes in expression of angiotensin receptor subtypes in the rat aorta during development. Biochem Biophys Res Commun 179(3):1361–1367CrossRefPubMedGoogle Scholar
  29. 29.
    Millis RM (2011) Epigenetics and hypertension. Curr Hypertens Rep 13(1):21–28CrossRefPubMedGoogle Scholar
  30. 30.
    Pojoga LH, Williams JS, Yao TM et al (2011) Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol 301(5):H1862–H1871CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Chu CH, Lo JF, Hu WS et al (2012) Histone acetylation is essential for ANG-II-induced IGF-IIR gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart. J Cell Physiol 227(1):259–268CrossRefPubMedGoogle Scholar
  32. 32.
    Lee HA, Lee DY, Lee HJ et al (2012) Enrichment of (pro)renin receptor promoter with activating histone codes in the kidneys of spontaneously hypertensive rats. J Renin Angiotensin Aldosterone Syst 13(1):11–18CrossRefPubMedGoogle Scholar
  33. 33.
    Lee HA, Cho HM, Lee DY et al (2012) Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications. Hypertension 59(3):621–626CrossRefPubMedGoogle Scholar
  34. 34.
    Batkai S, Thum T (2012) MicroRNAs in hypertension: mechanisms and therapeutic targets. Curr Hypertens Rep 14(1):79–87CrossRefPubMedGoogle Scholar
  35. 35.
    Bird A (2007) Perceptions of epigenetics. Nature 447(7143):396–398CrossRefPubMedGoogle Scholar
  36. 36.
    Marx V (2012) Epigenetics: reading the second genomic code. Nature 491(7422):143–147CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Fang Pei
    • 1
    • 2
    • 3
  • Xinquan Wang
    • 2
  • Rongchuan Yue
    • 2
  • Caiyu Chen
    • 2
  • Ji Huang
    • 3
  • Jie Huang
    • 3
  • Xiaohui Li
    • 1
    Email author
  • Chunyu Zeng
    • 2
    Email author
  1. 1.Institute of Materia Medica and Department of Pharmaceutics, College of PharmacyThird Military Medical UniversityChongqingChina
  2. 2.Department of Cardiology, Daping HospitalThird Military Medical UniversityChongqingChina
  3. 3.Department of CardiologyChongqing Corps Hospital of Chinese People’s Armed Police ForceChongqingChina

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