Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The protective effects of renin–angiotensin system componts on vascular calcification

Journal of Human Hypertension volume 35, pages 410–418 (2021)Cite this article

Subjects

Abstract

Renin–angiotensin system (RAS) has important roles in cardiovascular disease. Angiotensin II (Ang II) and angiotensin-(1–7) (Ang-(1–7)) are major effector peptides of RAS. However, the roles of Ang II type 2 receptor (AT2R) need to be further explored and the roles of Ang-(1–7) are still not very clear on vascular calcification (VC). Therefore, we hypothesized they have effects on preventing VC in vivo and in vitro. VC model is established by inorganic phosphate (IP) cultured with vascular smooth muscle cells (VSMC) for in vitro study and by 5/6 nephrectomy in mice for in vivo study. Increased calcified nodules by Alizarin Red S staining and mRNA expressions of bone morphogenetic protein-2 (BMP-2) and osteocalcin (OCN) by reverse transcription polymerase chain reaction in calcified WT VSMC were significantly inhibited in calcified AT2R overexpression (SmAT2) VSMC or after Ang-(1–7) treatment. After 5/6 nephrectomy, the ratio of positive and total area by Alizarin Red S and von Kossa staining and mRNA expressions of BMP-2 and OCN were significantly increased in ApoE/AT2R knockout mice compared with apolipoprotein E knockout mice, and which were significantly inhibited with Ang-(1–7) administration. Both AT2R and Ang-(1–7) have the effects on preventing VC induced by IP, at least in part through inhibiting BMP-2, OCN expressions, and in which Ang-(1–7) had protective roles mainly through Mas receptor rather than AT2R.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The formation of VSMC calcification cultured with calcified medium in WT and AT2R overexpression (SmAT2) mice for 14 days.
Fig. 2: The formation of aortic calcification after 5/6 nephrectomy in Apolipoprotein E knockout (ApoE) and ApoE/AT2R knockout (ApoE/AT2KO) mice for 6 weeks.
Fig. 3: The formation of calcified nodule in VSMC cultured with calcified medium in WT mice with or without Ang-(1–7) treatment for 14 days.
Fig. 4: The formation of aortic calcification after 5/6 nephrectomy in ApoE mice with or without Ang-(1–7) administration for 6 weeks.
Fig. 5: The formation of aortic calcification after 5/6 nephrectomy in ApoE/AT2KO mice with or without Ang-(1–7) administration for 6 weeks.

Similar content being viewed by others

References

  1. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transpl. 2000;15:1014–21.

    Article  CAS  Google Scholar 

  2. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478–83.

    Article  CAS  Google Scholar 

  3. Eggen DA, Strong JP, McGill HC Jr. Coronary calcification. Relationship to clinically significant coronary lesions and race, sex, and topographic distribution. Circulation. 1965;32:948–55.

    Article  CAS  Google Scholar 

  4. Moorthi RN, Moe SM. CKD-mineral and bone disorder: core curriculum 2011. Am J Kidney Dis. 2011;58:1022–36.

    Article  Google Scholar 

  5. Alfrey AC, Ibels LS. Role of phosphate and pyrophosphate in soft tissue calcification. Adv Exp Med Biol. 1978;103:187–93.

    Article  CAS  Google Scholar 

  6. Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, et al. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension. 2010;56:453–62.

    Article  CAS  Google Scholar 

  7. Larsson TE, Olauson H, Hagstrom E, Ingelsson E, Arnlov J, Lind L, et al. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol. 2010;30:333–9.

    Article  CAS  Google Scholar 

  8. Kendrick J, Chonchol M. The role of phosphorus in the development and progression of vascular calcification. Am J Kidney Dis. 2011;58:826–34.

    Article  CAS  Google Scholar 

  9. Sui YB, Chang JR, Chen WJ, Zhao L, Zhang BH, Yu YR, et al. Angiotensin-(1-7) inhibits vascular calcification in rats. Peptides. 2013;42:25–34.

    Article  CAS  Google Scholar 

  10. Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept. 2000;91:45–62.

    Article  CAS  Google Scholar 

  11. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 2003;100:8258–63.

    Article  CAS  Google Scholar 

  12. Zhang Z, Wang M, Fan XH, Chen JH, Guan YY, Tang YB. Upregulation of TRPM7 channels by angiotensin II triggers phenotypic switching of vascular smooth muscle cells of ascending aorta. Circ Res. 2012;111:1137–46.

    Article  CAS  Google Scholar 

  13. Feng W, Zhang K, Liu Y, Chen J, Cai Q, Zhang Y, et al. Apocynin attenuates angiotensin II-induced vascular smooth muscle cells osteogenic switching via suppressing extracellular signal-regulated kinase 1/2. Oncotarget. 2016;7:83588–600.

    Article  Google Scholar 

  14. Jia G, Stormont RM, Gangahar DM, Agrawal DK. Role of matrix Gla protein in angiotensin II-induced exacerbation of vascular calcification. Am J Physiol Heart Circ Physiol. 2012;303:H523–32.

    Article  CAS  Google Scholar 

  15. Carey RM. Update on angiotensin AT2 receptors. Curr Opin Nephrol Hypertens. 2017;26:91–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ameer OZ, Butlin M, Kaschina E, Sommerfeld M, Avolio AP, Phillips JK. Long-term angiotensin II receptor blockade limits hypertension, aortic dysfunction, and structural remodeling in a rat model of chronic kidney disease. J Vasc Res. 2016;53:216–29.

    Article  CAS  Google Scholar 

  17. Li M, Wu P, Shao J, Ke Z, Li D, Wu J. Losartan inhibits vascular calcification by suppressing the BMP2 and Runx2 expression in rats in vivo. Cardiovasc Toxicol. 2016;16:172–81.

    Article  CAS  Google Scholar 

  18. Armstrong ZB, Boughner DR, Drangova M, Rogers KA. Angiotensin II type 1 receptor blocker inhibits arterial calcification in a pre-clinical model. Cardiovasc Res. 2011;90:165–70.

    Article  CAS  Google Scholar 

  19. Matsushita K, Wu Y, Pratt RE, Dzau VJ. Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling. J Am Soc Hypertens. 2015;9:517–25.

    Article  CAS  Google Scholar 

  20. Kukida M, Mogi M, Kan-No H, Tsukuda K, Bai HY, Shan BS, et al. AT2 receptor stimulation inhibits phosphate-induced vascular calcification. Kidney Int. 2019;95:138–48.

    Article  CAS  Google Scholar 

  21. Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010;55:207–13.

    Article  CAS  Google Scholar 

  22. Chen Y, Kelm RJ Jr., Budd RC, Sobel BE, Schneider DJ. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem. 2004;92:178–88.

    Article  CAS  Google Scholar 

  23. Gava AL, Freitas FP, Balarini CM, Vasquez EC, Meyrelles SS. Effects of 5/6 nephrectomy on renal function and blood pressure in mice. Int J Physiol Pathophysiol Pharm. 2012;4:167–73.

    CAS  Google Scholar 

  24. Palit S, Kendrick J. Vascular calcification in chronic kidney disease: role of disordered mineral metabolism. Curr Pharm Des. 2014;20:5829–33.

    Article  CAS  Google Scholar 

  25. Amann K. Media calcification and intima calcification are distinct entities in chronic kidney disease. Clin J Am Soc Nephrol. 2008;3:1599–605.

    Article  Google Scholar 

  26. Shioi A, Nishizawa Y, Jono S, Koyama H, Hosoi M, Morii H. Beta-glycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1995;15:2003–9.

    Article  CAS  Google Scholar 

  27. Giachelli CM, Speer MY, Li X, Rajachar RM, Yang H. Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res. 2005;96:717–22.

    Article  CAS  Google Scholar 

  28. Shobeiri N, Adams MA, Holden RM. Vascular calcification in animal models of CKD: a review. Am J Nephrol. 2010;31:471–81.

    Article  Google Scholar 

  29. Stompor T. An overview of the pathophysiology of vascular calcification in chronic kidney disease. Perit Dial Int. 2007;27 (Suppl 2):S215–22.

    Article  Google Scholar 

  30. O’Brien KD, Probstfield JL, Caulfield MT, Nasir K, Takasu J, Shavelle DM, et al. Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med. 2005;165:858–62.

    Article  Google Scholar 

  31. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005;112 (Suppl 9):I229–34.

    PubMed  PubMed Central  Google Scholar 

  32. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension. 2001;38:938–42.

    Article  CAS  Google Scholar 

  33. Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci. 2011;121:297–303.

    Article  CAS  Google Scholar 

  34. Walters PE, Gaspari TA, Widdop RE. Angiotensin-(1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats. Hypertension. 2005;45:960–6.

    Article  CAS  Google Scholar 

  35. Bosnyak S, Widdop RE, Denton KM, Jones ES. Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. Int J Hypertension. 2012;2012:192567.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant Number 81570391).

Author information

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, China

    Hui-Yu Bai & Yi-Nong Jiang

  2. Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Hui-Yu Bai

  3. Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

    Bao-Shuai Shan

Authors
  1. Hui-Yu Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bao-Shuai Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi-Nong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-Nong Jiang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bai, HY., Shan, BS. & Jiang, YN. The protective effects of renin–angiotensin system componts on vascular calcification. J Hum Hypertens 35, 410–418 (2021). https://doi.org/10.1038/s41371-020-0347-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41371-020-0347-z

Search

Advanced search

Quick links