• Scott M. MacKenzieEmail author
  • Aurelie Nguyen Dinh Cat
  • Josie C. van Kralingen
  • Eleanor Davies


Aldosterone is a vitally important factor in cardiovascular homeostasis. Tightly regulated control of the biosynthesis and action of this mineralocorticoid hormone are crucial given that its excessive secretion, as seen in primary aldosteronism (PA), can result in severe hypertension, extensive organ damage and various comorbidities. The individual and societal consequences of this are huge: PA is currently held to account for ~15% of all hypertensive patients, but, due to difficulties in its accurate diagnosis, even this figure is likely to be an underestimate. Many patients are therefore currently classified as essential hypertensives and are receiving suboptimal treatment. Greater understanding of the regulatory systems governing aldosterone biosynthesis and action is therefore likely to be of huge benefit, leading to improved diagnostics, identification of informative biomarkers and development of better treatments more accurately targeted at the sizeable subsection of hypertensive patients most likely to benefit.

In this article we describe the major factors governing aldosterone biosynthesis and action in normal physiology and disease while also summarising significant recent advances in our understanding of PA and other promising current areas of research. It is our intention that this will provide insights into the highly dynamic state of current aldosterone research and the very real potential for game-changing treatments to counter the causes and consequences of excess aldosterone in the near future.


Aldosterone Hypertension Adrenal cortex Primary aldosteronism Angiotensin II Renin-angiotensin system ACTH 



S.M.M., J.C.v.K. and E.D. are members of the ENS@T-HT EU-funded Horizon 2020 research and innovation project into hypertension and personalised treatments (►


  1. 1.
    Connell JMC, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev. 2008;29:133–54.CrossRefGoogle Scholar
  2. 2.
    Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.CrossRefGoogle Scholar
  3. 3.
    Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol. 2014;4:1017–55.CrossRefGoogle Scholar
  4. 4.
    Stowasser M, Gordon RD. Primary aldosteronism: changing definitions and new concepts of physiology and pathophysiology both inside and outside the kidney. Physiol Rev. 2016;96:1327–84.CrossRefGoogle Scholar
  5. 5.
    MacKenzie SM, Freel EM, Connell JM, Fraser R, Davies E. ACTH and polymorphisms at steroidogenic loci as determinants of aldosterone secretion and blood pressure. Int J Mol Sci. 2017;18:579.CrossRefGoogle Scholar
  6. 6.
    Markou A, Sertedaki A, Kaltsas G, et al. Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension. J Clin Endocrinol Metab. 2015;100:2857–64.CrossRefGoogle Scholar
  7. 7.
    MacKenzie SM, Connell JMC, Davies E. Non-adrenal synthesis of aldosterone: a reality check. Mol Cell Endocrinol. 2011;350:163–7.CrossRefGoogle Scholar
  8. 8.
    Takeda Y, Demura M, Wang F, et al. Epigenetic regulation of aldosterone synthase gene by sodium and angiotensin II. J Am Heart Assoc. 2018;7:e008281.CrossRefGoogle Scholar
  9. 9.
    Robertson S, MacKenzie SM, Alvarez-Madrazo S, Diver LA, Lin J, Stewart PM, Fraser R, Connell JM, Davies E. MicroRNA-24 is a novel regulator of aldosterone and cortisol production in the human adrenal cortex. Hypertension. 2013;62:572–8.CrossRefGoogle Scholar
  10. 10.
    Lenzini L, Caroccia B, Campos AG, et al. Lower expression of the TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene is a hallmark of aldosterone-producing adenoma causing human primary aldosteronism. J Clin Endocrinol Metab. 2014;99:E674–82.CrossRefGoogle Scholar
  11. 11.
    Baker ME, Katsu Y. Evolution of the mineralocorticoid receptor: sequence, structure and function. J Endocrinol. 2017;234:T1–T16.CrossRefGoogle Scholar
  12. 12.
    Shibata S. Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron. J Endocrinol. 2017;234:T35–47.CrossRefGoogle Scholar
  13. 13.
    Chapman K, Holmes M, Seckl J. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013;93:1139–206.CrossRefGoogle Scholar
  14. 14.
    Ruhs S, Nolze A, Hübschmann R, Grossmann C. Nongenomic effects via the mineralocorticoid receptor. J Endocrinol. 2017;234:T107–24.CrossRefGoogle Scholar
  15. 15.
    Piaditis G, Markou A, Papanastasiou L, Androulakis II, Kaltsas G. Progress in aldosteronism: a review of the prevalence of primary aldosteronism in pre-hypertension and hypertension. Eur J Endocrinol. 2015;172:R191–203.CrossRefGoogle Scholar
  16. 16.
    Zennaro M-C, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism. J Endocrinol. 2015;224:R63–77.CrossRefGoogle Scholar
  17. 17.
    McManus F, Sands W, Diver L, MacKenzie SM, Fraser R, Davies E, Connell JM. APEX1 regulation of aldosterone synthase gene transcription is disrupted by a common polymorphism in humans. Circ Res. 2012;111:212–9.CrossRefGoogle Scholar
  18. 18.
    Tesch GH, Young MJ. Mineralocorticoid receptor signaling as a therapeutic target for renal and cardiac fibrosis. Front Pharmacol. 2017;8:313.CrossRefGoogle Scholar
  19. 19.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.CrossRefGoogle Scholar
  20. 20.
    DuPont JJ, Jaffe IZ. The role of the mineralocorticoid receptor in the vasculature. J Endocrinol. 2017;234:T67–82.CrossRefGoogle Scholar
  21. 21.
    Jia G, Habibi J, Aroor AR, Hill MA, Yang Y, Whaley-Connell A, Jaisser F, Sowers JR. Epithelial sodium channel in aldosterone-induced endothelium stiffness and aortic dysfunction. Hypertension. 2018;72:731–8. HYPERTENSIONAHA.118.11339CrossRefGoogle Scholar
  22. 22.
    Jia G, Aroor AR, Hill MA, Sowers JR. Role of renin-angiotensin-aldosterone system activation in promoting cardiovascular fibrosis and stiffness. Hypertension. 2018;122:624–38. HYPERTENSIONAHA.118.11065Google Scholar
  23. 23.
    Pitt B. Effect of aldosterone blockade in patients with systolic left ventricular dysfunction: implications of the RALES and EPHESUS studies. Mol Cell Endocrinol. 2004;217:53–8.CrossRefGoogle Scholar
  24. 24.
    Kolkhof P, Bärfacker L. Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol. 2017;234:T125–40.CrossRefGoogle Scholar
  25. 25.
    Bernhardt R. The potential of targeting CYP11B. Expert Opin Ther Targets. 2016;20:923–34. 14728222.2016.1151873CrossRefGoogle Scholar
  26. 26.
    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:1889–916.CrossRefGoogle Scholar
  27. 27.
    Funder JW. Primary aldosteronism: the next five years. Horm Metab Res. 2017;49:977–83.CrossRefGoogle Scholar
  28. 28.
    Miller WL. Steroidogenesis: unanswered questions. Trends Endocrinol Metab. 2017;28:771–93.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Scott M. MacKenzie
    • 1
    Email author
  • Aurelie Nguyen Dinh Cat
    • 1
  • Josie C. van Kralingen
    • 1
  • Eleanor Davies
    • 1
  1. 1.Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research CentreUniversity of GlasgowGlasgowUK

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