Calcium, Magnesium, and Oxidative Stress in Hyperaldosteronism
2005; Lippincott Williams & Wilkins; Volume: 111; Issue: 7 Linguagem: Inglês
10.1161/01.cir.0000157186.95918.78
ISSN1524-4539
AutoresErnesto L. Schiffrin, Rhian M. Touyz,
Tópico(s)Renal function and acid-base balance
ResumoHomeCirculationVol. 111, No. 7Calcium, Magnesium, and Oxidative Stress in Hyperaldosteronism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCalcium, Magnesium, and Oxidative Stress in Hyperaldosteronism Ernesto L. Schiffrin, MD, PhD, FRCPC and Rhian M. Touyz, MD, PhD Ernesto L. SchiffrinErnesto L. Schiffrin From the Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Québec, Canada. and Rhian M. TouyzRhian M. Touyz From the Canadian Institutes of Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Québec, Canada. Originally published22 Feb 2005https://doi.org/10.1161/01.CIR.0000157186.95918.78Circulation. 2005;111:830–831Hyperaldosteronism has been demonstrated to be associated with magnesium loss in the urine and hypomagnesemia1 as part of the syndrome of metabolic alkalosis and hypokalemia that characterizes this condition. In this issue of Circulation, Chhokar et al2 demonstrate the consequences of metabolic changes in rats subjected to aldosterone infusion in the presence of excess salt that result in hypocalcemia and hypomagnesemia, hyperparathyroidism, bone resorption, and calcium overload of tissues including the heart. This is associated with the enhanced production of reactive oxygen species (ROS) and an inflammatory phenotype, which then contribute to the decline in cardiac function and the progression to heart failure.See p 871Our knowledge of the (patho)physiological role of aldosterone and that of magnesium has increased dramatically during the past few years. The finding that aldosterone acts on target tissues other than the classic epithelial cells (kidney, colon) has had a profound influence on our understanding of the significance of aldosterone in cardiovascular disease. Aldosterone is now known to act on the heart and blood vessels, not only on muscle (smooth muscle and cardiomyocytes), but also on endothelial cells, where it induces nuclear swelling,3 which has been implicated in the mechanisms of vascular damage. Part of the effects of aldosterone may be mediated by the upregulation of endothelin-1 gene expression in the vasculature and the heart,4 as well as cross-talk with endothelin ETA receptors at the level of caveolae/lipid rafts.5 These effects occur through different mechanisms that may involve NADPH oxidase,6 xanthine oxidase,7 or mitochondrial sources of ROS,8 which result in the increased generation of free radicals. Increased oxidant stress may activate inflammatory mediators nuclear factor-κB and activator protein-1, which upregulate adhesion molecules and result in the vascular inflammatory phenotype.9 Furthermore, aldosterone may be produced locally in smooth muscle or heart.3 How these phenomena relate to mechanisms that lead to calcium and magnesium wasting and calcium overload after the development of hyperaldosteronism and whether they eventually contribute to oxidative stress remain unclear.Our understanding of the physiology of magnesium has undergone considerable progress in recent years as well. We now know that cellular magnesium is tightly controlled and stable under physiological conditions and that it plays a major role in regulating cardiovascular and renal function.10,11 Despite the fact that Mg2+ is the second most abundant intracellular cation and the predominant divalent cation, the molecular mechanisms that regulate cellular Mg2+ remain elusive. Transmembrane Mg2+ efflux has been linked to Na+-dependent Mg2+ exchanger activity,12,13 and paracellular renal Mg2+ transport is regulated by paracellin-1.14 Although studies of Mg2+ fluxes in mammalian cells have indicated the presence of functionally active plasma membrane Mg2+ transport mechanisms, the proteins responsible for these fluxes were unknown. This changed with the recent breakthrough that ion channel transient receptor potential melastatin (TRPM) 6 and TRPM7 are Mg2+-permeable ion channels involved in Mg2+ influx in epithelial and neuronal cells.15 TRPM6 and -7 are unique in that they are polypeptides with dual-function ion channel/protein kinases and have accordingly been termed chanzymes.16 TRPM6 is preferentially expressed in the small intestine, colon, and kidney, whereas TRPM7 is more widespread.17 TRPM7 is regulated by intracellular levels of Mg.ATP (adenosine triphosphate) and is strongly activated when Mg.ATP falls below 1 mmol/L.15 It was recently demonstrated that TRPM6 and -7 are expressed in vascular cells.18 Furthermore, TRPM7 is critically involved in vascular smooth muscle cell Mg2+ influx, and vascular TRPM6 and -7 are upregulated by aldosterone and angiotensin II.18 These findings are particularly interesting within the context of the study by Chhokar et al2 because they may provide insights into mechanisms underlying the hypomagnesemia and intracellular Mg2+ overload reported in aldosterone/salt-treated rats. It now is important to know whether in fact TRPM6 and -7 function is altered in hyperaldosteronism, and such studies certainly warrant further consideration.Chhokar et al2 demonstrate that lymphocyte generation of ROS (H2O2) is temporally linked to Ca2+ overload, suggesting a causal association between oxidant stress and a proinflammatory phenotype in hyperaldosteronism. Although it is tempting to attribute oxidative stress to intracellular Ca2+ excess, especially because mitochondrial matrix Ca2+ overload has been shown to enhance the generation of ROS,19 the present study did not establish a causal relationship between changes in calcium and oxidant excess. Mechanisms leading to the increased generation of ROS have been investigated in previous studies, and from these it appears that aldosterone itself, in the presence of inappropriate sodium intake or balance, will result in activation of NADPH oxidase, xanthine oxidase, or mitochondrial sources of ROS.20,21 Furthermore, changes in Mg2+ status may directly influence the cellular redox state. Mg2+ deficiency is associated with the increased production of ROS and the induction of immune and inflammatory reactions.22–24 The intermediate steps from mineralocorticoid receptors to the source of increased oxidant stress remain unclear. For other agents stimulating ROS generation such as angiotensin II, these pathways have been delineated and involve c-src,25 protein kinase C,26 and phospholipase D.27 Whether these molecular steps mediate some of the actions of aldosterone must be clarified by further studies. For the time being, the pathophysiological relationships involved in the association between hyperaldosteronism, calcium and magnesium wasting, tissue calcium overload (in particular, in the heart, leading to cardiac failure), and oxidative stress remain undefined. The study by Chhokar et al2 proposes an attractive hypothesis that requires further investigation.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Ernesto L. Schiffrin, MD, PhD, FRCPC, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, QC H2W 1R7, Canada. E-mail [email protected] References 1 Horton R, Biglieri EG. Effect of aldosterone on the metabolism of magnesium. J Clin Endocrinol Metab. 1962; 22: 1187–1192.CrossrefMedlineGoogle Scholar2 Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, Weber KT. Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation. 2005; 111: 871–878.LinkGoogle Scholar3 Rudolph AE, Blasi ER, Delyani JA. Tissue-specific corticosteroidogenesis in the rat. Mol Cell Endocrinol. 2000; 165: 221–224.CrossrefMedlineGoogle Scholar4 Park JB, Schiffrin EL. ETA receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension. 2001; 37: 1444–1449.CrossrefMedlineGoogle Scholar5 Callera GE, Tostes R, Schiffrin EL, Touyz RM. Aldosterone increases activation of vascular p38MAP kinase and NADPH oxidase via c-src–dependent processes: role of ETA receptors. Hypertension. 2004; 44: 514AGoogle Scholar6 Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.CrossrefMedlineGoogle Scholar7 Mervaala EM, Cheng ZJ, Tikkanen I, Lapatto R, Nurminen K, Vapaatalo H, Muller DN, Fiebeler A, Ganten U, Ganten D, Luft FC. 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Angiotensin II and vasopressin modulate intracellular free magnesium in vascular smooth muscle cells through Na+-dependent protein kinase C pathways. J Biol Chem. 1996; 271: 24353–14358.CrossrefMedlineGoogle Scholar13 Quamme GA, Dai LJ, Rabkin SW. Dynamics of intracellular free Mg2+ changes in a vascular smooth muscle cell line. Am J Physiol. 1993; 265: H281–H288.MedlineGoogle Scholar14 Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science. 1999; 285: 103–106.CrossrefMedlineGoogle Scholar15 Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell. 2003; 114: 191–200.CrossrefMedlineGoogle Scholar16 Cahalan MD. Cell biology. Channels as enzymes. Nature. 2001; 411: 542–543.CrossrefMedlineGoogle Scholar17 Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem. 2004; 279: 19–25.CrossrefMedlineGoogle Scholar18 He Y, Yao G, Savoia C, Touyz RM. Transient receptor potential melastatin 7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells: role of angiotensin II. Circ Res. Published online ahead of print December 9, 2004. DOI: 10.1161/01.RES.0000152967.88472.3e. Available at: http://circres.ahajournals.org/onlinefirst.shtml. Accessed January 21, 2005.Google Scholar19 Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004; 287: C817–C833.CrossrefMedlineGoogle Scholar20 Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL. Involvement of oxidative stress in the profibrotic action of aldosterone: interaction with the renin-angiotension system. Am J Hypertens. 2004; 17: 597–603.CrossrefMedlineGoogle Scholar21 Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol. 2002; 161: 1773–1781.CrossrefMedlineGoogle Scholar22 Maier JA, Malpuech-Brugere C, Zimowska W, Rayssiguier Y, Mazur A. Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acta. 2004; 1689: 13–21.CrossrefMedlineGoogle Scholar23 Touyz RM, Pu Q, He G, Chen X, Yao G, Neves MF, Viel E. Effects of low dietary magnesium intake on development of hypertension in stroke-prone spontaneously hypertensive rats: role of reactive oxygen species. J Hypertens. 2002; 20: 2221–2232.CrossrefMedlineGoogle Scholar24 Bussiere FI, Gueux E, Rock E, Girardeau JP, Tridon A, Mazur A, Rayssiguier Y. Increased phagocytosis and production of reactive oxygen species by neutrophils during magnesium deficiency in rats and inhibition by high magnesium concentration. Br J Nutr. 2002; 87: 107–113.CrossrefMedlineGoogle Scholar25 Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003; 23: 981–987.LinkGoogle Scholar26 Ungvari Z, Csiszar A, Kaminski PM, Wolin MS, Koller A. Chronic high pressure–induced arterial oxidative stress: involvement of protein kinase C–dependent NAD(P)H oxidase and local renin-angiotensin system. Am J Pathol. 2004; 165: 219–226.CrossrefMedlineGoogle Scholar27 Touyz RM, Schiffrin EL. Ang II–stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension. 1999; 34: 976–982.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wu S, Yu Y, Cai Y, Jia L, Wang X, Xiao C, Tang C and Qi Y (2012) Endogenous aldosterone is involved in vascular calcification in rat, Experimental Biology and Medicine, 10.1258/ebm.2011.011175, 237:1, (31-37), Online publication date: 1-Jan-2012. Yogi A, Callera G, O'Connor S, He Y, Correa J, Tostes R, Mazur A and Touyz R (2011) Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia, Journal of Hypertension, 10.1097/HJH.0b013e32834786d6, 29:7, (1400-1410), Online publication date: 1-Jul-2011. Sontia B, Montezano A, Paravicini T, Tabet F and Touyz R (2008) Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice, Hypertension, 51:4, (915-921), Online publication date: 1-Apr-2008. Guerrero-Romero F and Rodríguez-Morán M (2006) Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome, Diabetes/Metabolism Research and Reviews, 10.1002/dmrr.644, 22:6, (471-476), Online publication date: 1-Nov-2006. February 22, 2005Vol 111, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000157186.95918.78PMID: 15723988 Originally publishedFebruary 22, 2005 KeywordscalciumEditorialshyperaldosteronismreactive oxygen speciesmagnesiumPDF download Advertisement SubjectsHypertensionOxidant Stress
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