Skip to main content

Advertisement

SpringerLink
Log in

Mineralocorticoid receptor antagonism protects the aorta from vascular smooth muscle cell proliferation and collagen deposition in a rat model of adrenal aldosterone-producing adenoma

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 μg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF-β1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF-β1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bernini G, Galetta F, Franzoni F, Bardini M, Taurino C, Bernardini M, Ghiadoni L, Bernini M, Santoro G, Salvetti A (2008) Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism. J Hypertens 26(12):2399–2405. https://doi.org/10.1097/HJH.0b013e32831286fd

    Article  CAS  PubMed  Google Scholar 

  2. Castro NE, Kato M, Park JT, Natarajan R (2014) Transforming growth factor beta1 (TGF-beta1) enhances expression of profibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J Biol Chem 289(42):29001–29013. https://doi.org/10.1074/jbc.M114.600783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chiou TT, Chiang PH, Fuh M, Liu RT, Lee WC, Lee WC, Ng HY, Tsai YC, Chuang FR, Huang CC, Lee CT (2009) Factors determining cardiovascular and renal outcomes after adrenalectomy in patients with aldosterone-producing adrenal adenoma. Tohoku J Exp Med 218(1):17–24. https://doi.org/10.1620/tjem.218.17

    Article  CAS  PubMed  Google Scholar 

  4. Fuller PJ, Young MJ (2005) Mechanisms of mineralocorticoid action. Hypertension 46:1227–1235. https://doi.org/10.1161/01.hyp.0000193502.77417.17

    Article  CAS  PubMed  Google Scholar 

  5. Guazzoni G, Cestari A, Montorsi F, Lanzi R, Rigatti P, Kaouk JH, Gill IS (2001) Current role of laparoscopic adrenalectomy. Eur Urol 40(1):8–16. https://doi.org/10.1159/000049743

    Article  CAS  PubMed  Google Scholar 

  6. Hirano D, Hasegawa R, Igarashi T, Satoh K, Mochida J, Takahashi S, Yoshida T, Saitoh T, Kiyotaki S, Okada K (2015) Laparoscopic adrenalectomy for adrenal tumors: a 21-year single-institution experience. Asian J Surg 38(2):79–84. https://doi.org/10.1016/j.asjsur.2014.09.003

    Article  PubMed  Google Scholar 

  7. Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL (2004) Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system. Am J Hypertens 17(7):597–603. https://doi.org/10.1016/S0895-7061(04)00811-8

    CAS  PubMed  Google Scholar 

  8. Ishizawa K, Izawa Y, Ito H, Miki C, Miyata K, Fujita Y, Kanematsu Y, Tsuchiya K, Tamaki T, Nishiyama A, Yoshizumi M (2005) Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension 46:1046–1052. https://doi.org/10.1161/01.HYP.0000172622.51973.f5

    Article  CAS  PubMed  Google Scholar 

  9. Juknevicius I, Segal Y, Kren S, Lee R, Hostetter TH (2004) Effect of aldosterone on renal transforming growth factor-beta. Am J Physiol Renal Physiol 286(6):F1059–F1062. https://doi.org/10.1152/ajprenal.00202.2003

    Article  CAS  PubMed  Google Scholar 

  10. Lacolley P, Labat C, Pujol A, Delcayre C, Benetos A, Safar M (2002) Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats: effects of eplerenone. Circulation 106(22):2848–2853. https://doi.org/10.1161/01.CIR.0000039328.33137.6C

    Article  CAS  PubMed  Google Scholar 

  11. Leal Reyna M, Gomez RM, Lupi SN, Belli SH, Fenili CA, Martinez MS, Ruibal GF, Rossi MA, Chervin RA, Cornalo D, Contreras LN, Costa L, Nofal MT, Damilano SA, Pardes EM (2015) Screening for primary aldosteronism in an argentinian population: a multicenter prospective study. Arch Endocrinol Metab 59(5):441–447. https://doi.org/10.1590/2359-3997000000075

    Article  PubMed  Google Scholar 

  12. Lemos A, Leao M, Soares J, Palmeira A, Pinto M, Saraiva L, Sousa ME (2016) Medicinal chemistry strategies to disrupt the p53-MDM2/MDMX interaction. Med Res Rev 36(5):789–844. https://doi.org/10.1002/med.21393

    Article  CAS  PubMed  Google Scholar 

  13. Lumachi F, Ermani M, Basso SM, Armanini D, Iacobone M, Favia G (2005) Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg 71(10):864–869

    PubMed  Google Scholar 

  14. Meulmeester E, Jochemsen AG (2008) p53: a guide to apoptosis. Curr Cancer Drug Targets 8(2):87–97. https://doi.org/10.2174/156800908783769337

    Article  CAS  PubMed  Google Scholar 

  15. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr (2004) Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 89(3):1045–1050. https://doi.org/10.1210/jc.2003-031337

    Article  CAS  PubMed  Google Scholar 

  16. Nakamura Y, Suzuki S, Suzuki T, Ono K, Miura I, Satoh F, Moriya T, Saito H, Yamada S, Ito S, Sasano H (2006) MDM2: a novel mineralocorticoid-responsive gene involved in aldosterone-induced human vascular structural remodeling. Am J Pathol 169(2):362–371. https://doi.org/10.2353/ajpath.2006.051351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pu Q, Neves MF, Virdis A, Touyz RM, Schiffrin EL (2003) Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension 42:49–55. https://doi.org/10.1161/01.hyp.0000078357.92682.ec

    Article  CAS  PubMed  Google Scholar 

  18. Rizzoni D, Paiardi S, Rodella L, Porteri E, De Ciuceis C, Rezzani R, Boari GE, Zani F, Miclini M, Tiberio GA, Giulini SM, Rosei CA, Bianchi R, Rosei EA (2006) Changes in extracellular matrix in subcutaneous small resistance arteries of patients with primary aldosteronism. J Clin Endocrinol Metab 91(7):2638–2642. https://doi.org/10.1210/jc.2006-0101

    Article  CAS  PubMed  Google Scholar 

  19. Schiffrin EL (2006) Effects of aldosterone on the vasculature. Hypertension 47:312–318. https://doi.org/10.1161/01.HYP.0000201443.63240.a7

    Article  CAS  PubMed  Google Scholar 

  20. Schlumberger W, Thie M, Rauterberg J, Robenek H (1991) Collagen synthesis in cultured aortic smooth muscle cells. Modulation by collagen lattice culture, transforming growth factor-beta 1, and epidermal growth factor. Arterioscler Thromb 11(6):1660–1666. https://doi.org/10.1161/01.ATV.11.6.1660

    Article  CAS  PubMed  Google Scholar 

  21. Struthers A, Krum H, Williams GH (2008) A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol 31(4):153–158. https://doi.org/10.1002/clc.20324

    Article  PubMed  Google Scholar 

  22. Sun GP, Kohno M, Guo P, Nagai Y, Miyata K, Fan YY, Kimura S, Kiyomoto H, Ohmori K, Li DT, Abe Y, Nishiyama A (2006) Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury. J Am Soc Nephrol 17(8):2193–2201. https://doi.org/10.1681/asn.2005121375

    Article  CAS  PubMed  Google Scholar 

  23. Tsamis A, Krawiec JT, Vorp DA (2013) Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review. J R Soc Interface 10(83):20121004. https://doi.org/10.1098/rsif.2012.1004

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xu JF, Chen XQ, Du JZ, Wang TY (2005) CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats. Peptides 26(4):639–646. https://doi.org/10.1016/j.peptides.2004.11.014

    Article  CAS  PubMed  Google Scholar 

  25. Yan Y, Ouyang J, Wang C, Wu Z, Ma X, Li H, Xu H, Hu Z, Li J, Wang B, Shi T, Gong D, Ni D, Zhang X (2010) Aortic cell apoptosis in rat primary aldosteronism model. J Huazhong Univ Sci Technolog Med Sci 30(3):385–390. https://doi.org/10.1007/s11596-010-0362-3

    Article  PubMed  Google Scholar 

  26. Zhang X, Fu B, Lang B, Zhang J, Xu K, Li HZ, Ma X, Zheng T (2007) Technique of anatomical retroperitoneoscopic adrenalectomy with report of 800 cases. J Urol 177(4):1254–1257. https://doi.org/10.1016/j.juro.2006.11.098

    Article  PubMed  Google Scholar 

  27. Zhang X, Lang B, Ouyang JZ, Fu B, Zhang J, Xu K, Wang BJ, Ma X (2007) Retroperitoneoscopic adrenalectomy without previous control of adrenal vein is feasible and safe for pheochromocytoma. Urology 69(5):849–853. https://doi.org/10.1016/j.urology.2007.01.078

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Yongji Yan, Chao Wang, and Yiqin Lu contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, People’s Republic of China

    Yongji Yan & Huijie Gong

  2. Department of Urology, East Section of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, People’s Republic of China

    Yongji Yan & Huijie Gong

  3. Department of Urology, First People’s Hospital of Jining City, Jining, Shandong Province, People’s Republic of China

    Chao Wang

  4. Department of Gynecology, First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, People’s Republic of China

    Yiqin Lu

  5. Department of Urology, First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China

    Zhun Wu

  6. Department of Urology, Chinese People’s Liberation Army General Hospital, Military Postgraduate Medical College, 28 Fu Xing Road, Hai Dian District, Beijing, 100853, People’s Republic of China

    Xin Ma, Hongzhao Li, Baojun Wang & Xu Zhang

Authors
  1. Yongji Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiqin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huijie Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongzhao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Baojun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xu Zhang.

Ethics declarations

Conflict of interest statement

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Fig 1

Systolic blood pressure (SBP) changes of rats. CON, control; ALD, aldosterone; ALD + E, aldosterone plus eplerenone; ALD + H, aldosterone plus hydralazine. *P < 0.05 vs CON group, #P < 0.05 vs ALD group. (GIF 25 kb)

High resolution image (TIFF 161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, Y., Wang, C., Lu, Y. et al. Mineralocorticoid receptor antagonism protects the aorta from vascular smooth muscle cell proliferation and collagen deposition in a rat model of adrenal aldosterone-producing adenoma. J Physiol Biochem 74, 17–24 (2018). https://doi.org/10.1007/s13105-017-0600-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-017-0600-2

Keywords

Search

Navigation