Mineralocorticoid Receptor Antagonists and the Metabolic Syndrome
First Online: 19 June 2010 DOI:
Cite this article as: Tirosh, A., Garg, R. & Adler, G.K. Curr Hypertens Rep (2010) 12: 252. doi:10.1007/s11906-010-0126-2 Abstract
Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.
Keywords Aldosterone Mineralocorticoid receptor Obesity Insulin resistance Spironolactone Eplerenone References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
McNeill AM, Rosamond WD, Girman CJ, et al.: The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities study. Diabetes Care 2005, 28:385–390.
Chen J, Muntner P, Hamm LL, et al.: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004, 140:167–174.
Wilson PW, D’Agostino RB, Parise H, et al.: Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005, 112:3066–3072.
Wang J, Sarnola K, Ruotsalainen S, et al.: The metabolic syndrome predicts incident congestive heart failure: a 20-year follow-up study of elderly Finns. Atherosclerosis 2010, 210:237–242.
Wang J, Ruotsalainen S, Moilanen L, et al.: The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J 2007, 28:857–864.
Wannamethee SG, Shaper AG, Lennon L, Morris RW: Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005, 165:2644–2650.
Odermatt A, Atanasov AG: Mineralocorticoid receptors: emerging complexity and functional diversity. Steroids 2009, 74:163–171.
Grossmann C, Gekle M: New aspects of rapid aldosterone signaling. Mol Cell Endocrinol 2009, 308:53–62.
Gaddam KK, Pimenta E, Husain S, Calhoun DA: Aldosterone and cardiovascular disease. Curr Probl Cardiol 2009, 34:51–84.
Brown NJ: Aldosterone and vascular inflammation. Hypertension 2008, 51:161–167.
Funder JW: Reconsidering the roles of the mineralocorticoid receptor. Hypertension 2009, 53:286–290.
Leopold JA, Dam A, Maron BA, et al.: Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med 2007, 13:189–197.
Shibata S, Nagase M, Yoshida S, et al.: Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 2008, 14:1370–1376.
Lemarie CA, Simeone SM, Nikonova A, et al.: Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ Res 2009, 105:852–859.
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.
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.
Edwards NC, Steeds RP, Stewart PM, et al.: Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol 2009, 54:505–512.
Pitt B, Reichek N, Willenbrock R, et al.: Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003, 108:1831–1838.
Mehdi UF, Adams-Huet B, Raskin P, et al.: Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009, 20:2641–2650.
Bentley-Lewis R, Adler G, 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.
Caprio M, Feve B, Claes A, et al.: Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. FASEB J 2007, 21:2185–2194.
Lamounier-Zepter V, Ehrhart-Bornstein M, Bornstein SR: Mineralocorticoid-stimulating activity of adipose tissue. Best Pract Res Clin Endocrinol Metab 2005, 19:567–575.
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.
Goodfriend TL, Egan BM, Kelley DE: Plasma aldosterone, plasma lipoproteins, obesity and insulin resistance in humans. Prostaglandins Leukot Essent Fatty Acids 1999, 60:401–405.
Engeli S, Bohnke J, Gorzelniak K, et al.: Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005, 45:356–362.
Ferrannini E, Seghieri G, Muscelli E: Insulin and the renin-angiotensin-aldosterone system: influence of ACE inhibition. J Cardiovasc Pharmacol 1994, 24(Suppl 3):S61–S69.
Pierluissi J, Navas FO, Ashcroft SJ: Effect of adrenal steroids on insulin release from cultured rat islets of Langerhans. Diabetologia 1986, 29:119–121.
Matrozova J, Steichen O, Amar L, et al.: Fasting plasma glucose and serum lipids in patients with primary aldosteronism: a controlled cross-sectional study. Hypertension 2009, 53:605–610.
Catena C, Colussi G, Di Fabio A, et al.: Mineralocorticoid antagonists treatment versus surgery in primary aldosteronism. Horm Metab Res 2010 Jan 29 (Epub ahead of print).
Giacchetti G, Sechi LA, Rilli S, Carey RM: The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab 2005, 16:120–126.
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.
• Fallo F, Della Mea P, Sonino N, et al.: Adiponectin and insulin sensitivity in primary aldosteronism. Am J Hypertens 2007, 20:855–861.
Patients with primary aldosteronism had more insulin resistance (higher HOMA index) and lower levels of adiponectin than patients with low-renin essential hypertension in the absence of MetS
Sindelka G, Widimsky J, Haas T, et al.: Insulin action in primary hyperaldosteronism before and after surgical or pharmacological treatment. Exp Clin Endocrinol Diabetes 2000, 108:21–25.
•• Garg R, Hurwitz S, Williams GH, et al.: Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab 2010, 95:1986–1990.
In normotensive healthy adults, high angiotensin II–stimulated aldosterone level was an independent predictor of insulin resistance even after adjusting for age, body mass index, and diastolic blood pressure
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.
Selvaraj J, Muthusamy T, Srinivasan C, Balasubramanian K: Impact of excess aldosterone on glucose homeostasis in adult male rat. Clin Chim Acta 2009, 407:51–57.
Ndisang JF, Lane N, Jadhav A: The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. Endocrinology 2009, 150:2098–2108.
•• 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.
In obese, db/db mice, MR blockade reduced circulating triglyceride levels, decreased adipose tissue expression of inflammatory cytokines, and increased expression of adiponectin and PPARγ. In 3 T3-L1 preadipocytes, aldosterone increased expression of inflammatory cytokines and decreased expression of adiponectin and PPARγ, supporting a direct effect of aldosterone on gene expression
•• 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.
In obese, db/db and ob/ob mice, MR blockade reduced insulin resistance and improved adipose tissue inflammation (decreased reactive oxygen species and macrophage infiltration). In 3 T3-L1 adipocytes, aldosterone increased intracellular reactive oxygen species
Calle C, Campion J, Garcia-Arencibia M, et al.: Transcriptional inhibition of the human insulin receptor gene by aldosterone. J Steroid Biochem Mol Biol 2003, 84:543–553.
• 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.
Aldosterone treatment in the adipocyte cell line resulted in IRS-1 serine phosphorylation and degradation, leading to decreased insulin stimulation of both Akt activation and glucose uptake. This mechanism was suggested to involve aldosterone-mediated intracellular oxidative stress
Sato A, Fukuda S: Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension. J Hum Hypertens 2009 Oct 29 (Epub ahead of print).
• 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.
MR blockade improved glucose metabolism (assessed by the glucose tolerance test and insulin tolerance test), reduced triglyceride and cholesterol levels, reduced hepatic inflammation (decreased hepatic expression of TNFα, interleukin-6, and MCP-1), and reduced hepatic steatosis in mice fed a high-fat and high-fructose diet
Kirilmaz B, Asgun F, Alioglu E, et al.: High inflammatory activity related to the number of metabolic syndrome components. J Clin Hypertens (Greenwich) 2010, 12:136–144.
Caprio M, Newfell BG, la Sala A, et al.: Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ Res 2008, 102:1359–1367.
•• Limor R, Kaplan M, Sharon O, et al.: Aldosterone up-regulates 12- and 15-lipoxygenase expression and LDL oxidation in human vascular smooth muscle cells. J Cell Biochem 2009, 108:1203–1210.
Treating vascular smooth muscle cells with aldosterone resulted in increased expression of 12- and 15-lipoxygenase expression and increased LDL oxidation. These effects were blocked by MR antagonists or an EGF-receptor antagonist, demonstrating potential interactions between these two receptors
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.
Izawa H, Murohara T, Nagata K, et al.: Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 2005, 112:2940–2945.
Grandi AM, Imperiale D, Santillo R, et al.: Aldosterone antagonist improves diastolic function in essential hypertension. Hypertension 2002, 40:647–652.
• The NAVIGATOR Study Group: Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010, 363:1477–1490.
In this large, placebo-controlled, randomized trial among patients with impaired glucose tolerance (many of whom met the MetS diagnostic criteria), the use of valsartan for 5 years led to a relative reduction of 14% in the incidence of diabetes. This study supports a role for blockade of the RAAS in preventing progression to diabetes
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