Aldosterone in salt-sensitive hypertension and metabolic syndrome

Review

Abstract

Metabolic syndrome, which is caused by obesity, is now a global pandemic. Metabolic syndrome is an aggregation of hypertension, diabetes and dyslipidaemia. Insulin resistance is a key factor in the development of these components of metabolic syndrome. Concerning the mechanism for the development of hypertension in metabolic syndrome, the lack of insulin resistance in the kidney increases sodium reabsorption by hyperinsulinaemia, leading to sodium retention in the body, and resultant salt-sensitive hypertension. Moreover, hyperaldosteronism, which is caused by adipocyte-derived aldosterone-releasing factors, induces not only salt-sensitive hypertension, but also proteinuria in obese hypertensive rats. Salt loading markedly aggravates proteinuria and induces cardiac diastolic dysfunction in obese hypertensive rats, suggesting that salt and aldosterone exert unfavourable synergistic actions on the cardiovascular system, possibly through the overproduction of oxidative stress. In turn, reactive oxygen species (ROS), which are induced by adipokines such as tumour necrosis factor-α, non-esterified fatty acids, angiotensinogen etc., can activate the mineralocorticoid (MR) receptor, in an aldosterone-independent fashion. Therefore, aldosterone/MR activation plays a key role not only in the development of salt-sensitive hypertension, but also in cardiovascular injury in metabolic syndrome, possibly through its function as a feed-forward system.

Keywords

Aldosterone Oxidative stress Salt Hypertension Proteinuria Metabolic syndrome 

References

  1. 1.
    Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716PubMedCrossRefGoogle Scholar
  2. 2.
    Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J (2004) The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 140:167–174PubMedGoogle Scholar
  3. 3.
    Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T (2006) Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol 17:3438–3446PubMedCrossRefGoogle Scholar
  4. 4.
    Nagase M, Matsui H, Shibata S, Gotoda T, Fujita T (2007) Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension 50:877–883PubMedCrossRefGoogle Scholar
  5. 5.
    Natali A, Quiñones Galvan A, Santoro D, Pecori N, Taddei S, Salvetti A, Ferrannini E (1993) Relationship between insulin release, antinatriuresis and hypokalaemia after glucose ingestion in normal and hypertensive man. Clin Sci (Lond) 85:327–335Google Scholar
  6. 6.
    Zheng Y, Yamada H, Sakamoto K, Horita S, Kunimi M, Endo Y, Li Y, Tobe K, Terauchi Y, Kadowaki T, Seki G, Fujita T (2005) Roles of insulin receptor substrates in insulin-induced stimulation of renal proximal bicarbonate absorption. J Am Soc Nephrol 16:2288–2295PubMedCrossRefGoogle Scholar
  7. 7.
    Uzu T, Kimura G, Yamauchi A, Kanasaki M, Isshiki K, Araki S, Sugiomoto T, Nishio Y, Maegawa H, Koya D, Haneda M, Kashiwagi A (2006) Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. J Hypertens 24:1627–1632PubMedCrossRefGoogle Scholar
  8. 8.
    Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M (1989) The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 321:580–585PubMedGoogle Scholar
  9. 9.
    Strazzullo P, Barbato A, Galletti F, Barba G, Siani A, Iacone R, D’Elia L, Russo O, Versiero M, Farinaro E, Cappucio FP (2006) Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart study. J Hypertens 24:1633–1639PubMedCrossRefGoogle Scholar
  10. 10.
    DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ (1975) The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 55:845–855PubMedCrossRefGoogle Scholar
  11. 11.
    Hall JE, Kuo JJ, da Silva AA, de Paula RB, Liu J, Tallam L (2003) Obesity-associated hypertension and kidney disease. Curr Opin Nephrol Hypertens 12:195–200PubMedCrossRefGoogle Scholar
  12. 12.
    de Paula RB, da Silva AA, Hall JE (2004) Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43:41–47PubMedCrossRefGoogle Scholar
  13. 13.
    Connell JMC, Davies E (2005) The new biology of aldosterone. J Endocrinol 186:1–20PubMedCrossRefGoogle Scholar
  14. 14.
    Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T (2007) Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension 49:355–364PubMedCrossRefGoogle Scholar
  15. 15.
    Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA, Bornstein SR (2003) Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A 100:14211–14216PubMedCrossRefGoogle Scholar
  16. 16.
    Verhave JC, Hillege HL, Burgerhof JGM, Janssen WMT, Gansevoort RT, Navis GJ, de Zeeuw D, de Jong PE; PRVEND Study Group (2004) Sodium intake affects urinary albumin excretion especially in overweight subjects. J Intern Med 256:324–330PubMedCrossRefGoogle Scholar
  17. 17.
    Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T, Fujita T (2006) Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension 47:1084–1093PubMedCrossRefGoogle Scholar
  18. 18.
    Funder JW (2004) Is aldosterone bad for the heart? Trends Endocrinol Metab 15:139–142PubMedCrossRefGoogle Scholar
  19. 19.
    Bossis G, Melchior F (2006) Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol Cell 21:349–357PubMedCrossRefGoogle Scholar
  20. 20.
    Pitt B (2004) Effect of aldosterone blockade in patients with systolic left ventricular dysfunction: implications of the RALES and EPHESUS studies. Mol Cell Endocrinol 217:53–58PubMedCrossRefGoogle Scholar
  21. 21.
    Bochud M, Nussberger J, Bovet P, Maillard MR, Elston RC, Paccaud F, Shamlaye C, Burnier M (2006) Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension 48:239–245PubMedCrossRefGoogle Scholar
  22. 22.
    Onozato ML, Tojo A, Kobayashi N, Goto A, Matsuoka H, Fujita T (2007) Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney. Nephrol Dial Transplant 22:1314–1322PubMedCrossRefGoogle Scholar
  23. 23.
    Epstein M, Buckalew V, Martinez F, Altamirano J, Roniker B, Kleiman J, Krause S (2002) Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria. Am J Hypertens 15:24ACrossRefGoogle Scholar
  24. 24.
    Hinokio Y, Suzuki S, Hirai M, Suzuki C, Suzuki M, Toyota T (2002) Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy. Diabetologia 45:877–882PubMedCrossRefGoogle Scholar
  25. 25.
    Ogihara T, Asano T, Ando K, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Katagiri H, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Komuro I, Fujita T (2002) Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 40:872–879PubMedCrossRefGoogle Scholar
  26. 26.
    Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, Ono H, Fujishiro M, Kushiyama A, Fukushima A, Kikuchi M, Noguchi N, Aburatani H, Gotoh Y, Komuro I, Fujita T (2004) Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabatologia 47:794–805CrossRefGoogle Scholar
  27. 27.
    Roberge C, Carpentier AC, Langlois MF, Baillargeon JP, Ardilouze JL, Maheux P, Gallo-Payet N (2007) Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Am J Physiol Endocrinol Metab 293:E1465–E1478PubMedCrossRefGoogle Scholar
  28. 28.
    Jaffe IZ, Mendelsohn ME (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643–650PubMedCrossRefGoogle Scholar
  29. 29.
    Sugiyama T, Yoshimoto T, Tsuchiya K, Gochou N, Hirono Y, Tateno T, Fukai N, Shichiri M, Hirata Y (2005) Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology 146:3900–3906PubMedCrossRefGoogle Scholar
  30. 30.
    Fareh J, Touyz RM, Schiffrin EL, Thibault G (1997) Cardiac type-1 angiotensin II receptor status in deoxycorticosterone acetate-salt hypertension in rats. Hypertension 30:1253–1259PubMedGoogle Scholar
  31. 31.
    Rocha R, Martin-Berger CL, Yang P, Scherrer R, Delyani J, McMahon E (2002) Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 143:4828–4836PubMedCrossRefGoogle Scholar
  32. 32.
    Velasquez MT, Striffler JS, Abraham AA, Michaelis OE, Scalbert E, Thibault N (1997) Perindopril ameliorates glomerular and renal tubulointerstitial injury in the SHR/N-corpulent rat. Hypertension 30:1232–1237PubMedGoogle Scholar
  33. 33.
    Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109:1417–1427PubMedGoogle Scholar
  34. 34.
    Peters B, Grisk O, Becher B, Wanka H, Kuttler B, Lüdemann J, Lorenz G, Retting R, Mullins JJ, Peters J (2008) Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis. J Hypertens 26:102–109PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Nephrology and EndocrinologyUniversity of TokyoTokyoJapan

Personalised recommendations