Skip to main content

Advertisement

Log in

The Role of Aldosterone in the Metabolic Syndrome

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

The metabolic syndrome associates metabolic abnormalities such as insulin resistance and dyslipidemia with increased waist circumference and hypertension. It is a major public health concern, as its prevalence could soon reach 30% to 50% in developed countries. Aldosterone, a mineralocorticoid hormone classically involved in sodium balance regulation, is increased in patients with metabolic syndrome. Besides its classic actions, aldosterone and mineralocorticoid receptor (MR) activation affect glucose metabolism, inducing insulin resistance through various mechanisms that involve oxidative stress, inflammation, and downregulation of proteins involved in insulin signaling pathways. Aldosterone and MR signaling exert deleterious effects on the cardiovascular system and the kidney that influence the cardiovascular risk associated with metabolic syndrome. Salt load plays a major role in cardiovascular injury induced by aldosterone and MR signaling. Large multicenter, randomized clinical trials testing the beneficial effects of MR antagonists on cardiovascular events and mortality in patients with metabolic syndrome are needed.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Recently published papers of interest have been highlighted as: • Of importance •• Of major importance

  1. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2010, 375:181–183.

    Article  PubMed  Google Scholar 

  2. •• Alberti KG, Eckel RH, Grundy SM, et al.: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120:1640–1645. This paper is of particular interest, as it describes the new diagnostic criteria for the metabolic syndrome.

    Article  PubMed  CAS  Google Scholar 

  3. Lakka HM, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288:2709–2716.

    Article  PubMed  Google Scholar 

  4. • Motillo S, Filion KB, Genest J, et al.: The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol 2010, 56:1113–1132. This recent meta-analysis described the high cardiovascular risk associated with the metabolic syndrome, using the definition of the National Cholesterol Education Program.

    Article  Google Scholar 

  5. Briet M, Schiffrin EL: Aldosterone: effects on the kidney and cardiovascular system. Nat.Rev.Nephrol. 2010, 6:261–273.

    Article  PubMed  CAS  Google Scholar 

  6. Ingelsson E, Pencina MJ, Tofler GH, et al.: Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study. Circulation 2007, 116:984–992.

    Article  PubMed  CAS  Google Scholar 

  7. Chartier L, Schiffrin E, Thibault G, et al.: Atrial natriuretic factor inhibits the stimulation of aldosterone secretion by angiotensin II, ACTH and potassium in vitro and angiotensin II-induced steroidogenesis in vivo. Endocrinology 1984, 115:2026–2028.

    Article  PubMed  CAS  Google Scholar 

  8. • Urbanet R, Pilon C, Calcagno A, et al.: Analysis of insulin sensitivity in adipose tissue of patients with primary aldosteronism. J Clin Endocrinol Metab 2010, 95:4037–4042. This study is the first one to test insulin sensitivity in adipose tissue obtained from patients with primary aldosteronism and controls. The authors did not demonstrate insulin resistance in vitro after aldosterone administration in primary adipocyte cell culture.

    Article  PubMed  CAS  Google Scholar 

  9. •• Funder JW: Reconsidering the roles of the mineralocorticoid receptor. Hypertension 2009, 53:286–290. This review raises the important question of the role of glucocorticoids acting through MR activation.

    Google Scholar 

  10. Edwards CR, Stewart PM, Burt D, et al.: Localisation of 11 beta-hydroxysteroid dehydrogenase—tissue specific protector of the mineralocorticoid receptor. Lancet 1988, 2:986–989.

    Article  PubMed  CAS  Google Scholar 

  11. Veilleux A, Laberge PY, Morency J, et al.: Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue. J Steroid Biochem Mol Biol 2010, 122:28–34.

    Article  PubMed  CAS  Google Scholar 

  12. Funder J, Myles K: Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies. Endocrinology 1996, 137:5264–5268.

    Article  PubMed  CAS  Google Scholar 

  13. Funder JW, Reincke M: Aldosterone: a cardiovascular risk factor? Biochim Biophys Acta 2010, 1802:1188–1192.

    PubMed  CAS  Google Scholar 

  14. Tuck ML, Sowers J, Dornfeld L, et al.: The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981, 304:930–933.

    Article  PubMed  CAS  Google Scholar 

  15. Rossi GP, Belfiore A, Bernini G, et al.: Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J Clin Endocrinol Metab 2008, 93:2566–2571.

    Article  PubMed  CAS  Google Scholar 

  16. Bentley-Lewis R, Adler GK, Perlstein T, et al.: Body mass index predicts aldosterone production in normotensive adults on a high-salt diet. J Clin Endocrinol Metab 2007, 92:4472–4475.

    Article  PubMed  CAS  Google Scholar 

  17. Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ: Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res 1999, 7:355–362.

    PubMed  CAS  Google Scholar 

  18. Engeli S, Bohnke J, Gorzelniak K, et al.: Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005, 45:356–362.

    Article  PubMed  CAS  Google Scholar 

  19. Gorzelniak K, Engeli S, Janke J, et al.: Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension. J Hypertens 2002, 20:965–973.

    Article  PubMed  CAS  Google Scholar 

  20. Petrasek D, Jensen G, Tuck M, Stern N: In vitro effects of insulin on aldosterone production in rat zona glomerulosa cells. Life Sci 1992, 50:1781–1787.

    Article  PubMed  CAS  Google Scholar 

  21. Colussi G, Catena C, Lapenna R, et al.: Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care 2007, 30:2349–2354.

    Article  PubMed  CAS  Google Scholar 

  22. Goodfriend TL, Egan B, Stepniakowski K, Ball DL: Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. Hypertension 1995, 25:30–36.

    PubMed  CAS  Google Scholar 

  23. • Jeon JH, Kim KY, Kim JH, et al.: A novel adipokine CTRP1 stimulates aldosterone production. FASEB J 2008, 22:1502–1511. This paper provides one of the explanations for the link between obesity and aldosterone synthesis. The authors demonstrated that C1q TNF-related protein (CTRP)1, an adipokine, stimulates the synthesis of aldosterone by cells from the human adrenal cortical cell line H295R.

    Article  PubMed  CAS  Google Scholar 

  24. Goodfriend TL, Ball DL, Raff H, et al.: Oxidized products of linoleic acid stimulate adrenal steroidogenesis. Endocr Res 2002, 28:325–330.

    Article  PubMed  CAS  Google Scholar 

  25. Goodfriend TL, Ball DL, Egan BM, et al.: Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Hypertension 2004, 43:358–363.

    Article  PubMed  CAS  Google Scholar 

  26. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, et al.: Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A 2003, 100:14211–14216.

    Article  PubMed  CAS  Google Scholar 

  27. Devenport LD, Goodwin KG, Hopkins PM: Continuous infusion of aldosterone: correlates of body weight gain. Pharmacol Biochem Behav 1985, 22:707–709.

    Article  PubMed  CAS  Google Scholar 

  28. Caprio M, Feve B, Claes A, et al.: Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. FASEB J 2007, 21:2185–2194.

    Article  PubMed  CAS  Google Scholar 

  29. Berg AH, Scherer PE: Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005, 96:939–949.

    Article  PubMed  CAS  Google Scholar 

  30. Abbasi A, Corpeleijn E, Postmus D, et al.: Plasma procalcitonin is associated with obesity, insulin resistance, and the metabolic syndrome. J Clin Endocrinol Metab 2010, 95:E26–E31.

    Article  PubMed  Google Scholar 

  31. Guo C, Ricchiuti V, Lian BQ, et al.: Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation 2008, 117:2253–2261.

    Article  PubMed  CAS  Google Scholar 

  32. Hirata A, Maeda N, Hiuge A, et al.: Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice. Cardiovasc Res 2009, 84:164–172.

    Article  PubMed  CAS  Google Scholar 

  33. Takebayashi K, Matsumoto S, Aso Y, Inukai T: Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab 2006, 91:2214–2217.

    Article  PubMed  CAS  Google Scholar 

  34. • Savoia C, Touyz RM, Amiri F, Schiffrin EL: Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. Hypertension 2008, 51:432–439. This clinical study involving hypertensive patients demonstrated the beneficial effect of eplerenone, an MR blocker, on inflammation and resistance artery stiffness.

    Article  PubMed  CAS  Google Scholar 

  35. Conn JW: Hypertension, the potassium ion and impaired carbohydrate tolerance. N Engl J Med 1965, 273:1135–1143.

    Article  PubMed  CAS  Google Scholar 

  36. Fallo F, Veglio F, Bertello C, et al.: Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 2006, 91:454–459.

    Article  PubMed  CAS  Google Scholar 

  37. Catena C, Lapenna R, Baroselli S, et al.: Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab 2006, 91:3457–3463.

    Article  PubMed  CAS  Google Scholar 

  38. Freel EM, Tsorlalis IK, Lewsey JD, et al.: Aldosterone status associated with insulin resistance in patients with heart failure—data from the ALOFT study. Heart 2009, 95:1920–1924.

    Article  PubMed  CAS  Google Scholar 

  39. Garg R, Hurwitz S, Williams GH, et al.: Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab 2010, 95:1986–1990.

    Article  PubMed  CAS  Google Scholar 

  40. Ranade K, Wu KD, Risch N, et al.: Genetic variation in aldosterone synthase predicts plasma glucose levels. Proc Natl Acad Sci U S A 2001, 98:13219–13224.

    Article  PubMed  CAS  Google Scholar 

  41. Kraus D, Jager J, Meier B, et al.: Aldosterone inhibits uncoupling protein-1, induces insulin resistance, and stimulates proinflammatory adipokines in adipocytes. Horm Metab Res 2005, 37:455–459.

    Article  PubMed  CAS  Google Scholar 

  42. Lastra G, Whaley-Connell A, Manrique C, et al.: Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat. Am J Physiol Endocrinol Metab 2008, 295:E110–E116.

    Article  PubMed  CAS  Google Scholar 

  43. Wada T, Ohshima S, Fujisawa E, et al.: Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3 T3-L1 adipocytes. Endocrinology 2009, 150:1662–1669.

    Article  PubMed  CAS  Google Scholar 

  44. Hitomi H, Kiyomoto H, Nishiyama A, et al.: Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension 2007, 50:750–755.

    Article  PubMed  CAS  Google Scholar 

  45. Yamashita R, Kikuchi T, Mori Y, et al.: Aldosterone stimulates gene expression of hepatic gluconeogenic enzymes through the glucocorticoid receptor in a manner independent of the protein kinase B cascade. Endocr J 2004, 51:243–251.

    Article  PubMed  CAS  Google Scholar 

  46. • Wada T, Kenmochi H, Miyashita Y, et al.: Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology 2010, 151:2040–2049. The authors demonstrated the role of MR activation in hepatic steatosis, inflammation, and oxidative stress in mice receiving a high-fat and high-fructose diet. They also demonstrated that MR activation is implicated in hepatic gluconeogenesis, which could participate in the impairment of glucose metabolism associated with metabolic syndrome.

    Article  PubMed  CAS  Google Scholar 

  47. Bochud M, Nussberger J, Bovet P, et al.: Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension 2006, 48:239–245.

    Article  PubMed  CAS  Google Scholar 

  48. Kathiresan S, Larson MG, Benjamin EJ, et al.: Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study. Am J Hypertens 2005, 18:657–665.

    Article  PubMed  CAS  Google Scholar 

  49. Joffe HV, Kwong RY, Gerhard-Herman MD, et al.: Beneficial effects of eplerenone versus hydrochlorothiazide on coronary circulatory function in patients with diabetes mellitus. J Clin Endocrinol Metab 2007, 92:2552–2558.

    Article  PubMed  CAS  Google Scholar 

  50. Matsumoto S, Takebayashi K, Aso Y: The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism 2006, 55:1645–1652.

    Article  PubMed  CAS  Google Scholar 

  51. Matsui H, Ando K, Kawarazaki H, et al.: Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. Hypertension 2008, 52:287–294.

    Article  PubMed  CAS  Google Scholar 

  52. Pitt B, Remme W, Zannad F, et al.: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003, 348:1309–1321.

    Article  PubMed  CAS  Google Scholar 

  53. Pitt B, Zannad F, Remme WJ, et al.: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999, 341:709–717.

    Article  PubMed  CAS  Google Scholar 

  54. Young M, Fullerton M, Dilley R, Funder J: Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 1994, 93:2578–2583.

    Article  PubMed  CAS  Google Scholar 

  55. Brilla CG, Weber KT: Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992, 120:893–901.

    PubMed  CAS  Google Scholar 

  56. Nakano S, Kobayashi N, Yoshida K, et al.: Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats. Hypertens Res 2005, 28:925–936.

    Article  PubMed  CAS  Google Scholar 

  57. Endemann DH, Touyz RM, Iglarz M, et al.: Eplerenone prevents salt-induced vascular remodeling and cardiac fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension 2004, 43:1252–1257.

    Article  PubMed  CAS  Google Scholar 

  58. Somers MJ, Mavromatis K, Galis ZS, Harrison DG: Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation 2000, 101:1722–1728.

    PubMed  CAS  Google Scholar 

  59. Beswick RA, Zhang H, Marable D, et al.: Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension 2001, 37:781–786.

    PubMed  CAS  Google Scholar 

  60. Sun Y, Zhang J, Lu L, et al.: Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am J Pathol 2002, 161:1773–1781.

    Article  PubMed  CAS  Google Scholar 

  61. Ammarguellat F, Larouche I, Schiffrin EL: Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ET(A) receptor antagonism. Circulation 2001, 103:319–324.

    PubMed  CAS  Google Scholar 

  62. Park JB, Schiffrin EL: Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens 2002, 15:164–169.

    Article  PubMed  CAS  Google Scholar 

  63. Pu Q, Neves MF, Virdis A, et al.: Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension 2003, 42:49–55.

    Article  PubMed  CAS  Google Scholar 

  64. Greene EL, Kren S, Hostetter TH: Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996, 98:1063–1068.

    Article  PubMed  CAS  Google Scholar 

  65. Nishiyama A, Yao L, Nagai Y, et al.: Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension 2004, 43:841–848.

    Article  PubMed  CAS  Google Scholar 

  66. Shibata S, Nagase M, Yoshida S, et al.: Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension 2007, 49:355–364.

    Article  PubMed  CAS  Google Scholar 

  67. Nagase M, Yoshida S, Shibata S, et al.: Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J.Am.Soc.Nephrol. 2006, 17:3438–3446.

    Google Scholar 

  68. Gross ML, Ritz E, Schoof A, et al.: Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes. Lab Invest 2004, 84:452–464.

    Article  PubMed  CAS  Google Scholar 

  69. Nagase M, Matsui H, Shibata S, et al.: Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension 2007, 50:877–883.

    Article  PubMed  CAS  Google Scholar 

Download references

Source of Funding

The work of the authors was supported by Canadian Institutes of Health Research (CIHR) grants MOP37137, MOP82790, and MOP102606; a Canada Research Chair (CRC) on Hypertension and Vascular Research from the CIHR/CRC Program of the Government of Canada; the Canada Fund for Innovation (E.L.S.); and a Fellowship from the Heart and Stroke Foundation of Canada (M.B.).

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marie Briet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Briet, M., Schiffrin, E.L. The Role of Aldosterone in the Metabolic Syndrome. Curr Hypertens Rep 13, 163–172 (2011). https://doi.org/10.1007/s11906-011-0182-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-011-0182-2

Keywords

Navigation