Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury

James M Luther, Pengcheng Luo, Zuofei Wang, Samuel E Cohen, Hyung-Suk Kim, Agnes B Fogo, Nancy J Brown, James M Luther, Pengcheng Luo, Zuofei Wang, Samuel E Cohen, Hyung-Suk Kim, Agnes B Fogo, Nancy J Brown

Abstract

Angiotensin II causes cardiovascular injury in part by aldosterone-induced mineralocorticoid receptor activation, and it can also activate the mineralocorticoid receptor in the absence of aldosterone in vitro. Here we tested whether endogenous aldosterone contributes to angiotensin II/salt-induced cardiac, vascular, and renal injury by the mineralocorticoid receptor. Aldosterone synthase knockout mice and wild-type littermates were treated with angiotensin II or vehicle plus the mineralocorticoid receptor antagonist spironolactone or regular diet while drinking 0.9% saline. Angiotensin II/salt caused hypertension in both the knockout and wild-type mice, an effect significantly blunted in the knockout mice. Either genetic aldosterone deficiency or mineralocorticoid receptor antagonism reduced cardiac hypertrophy, aortic remodeling, and albuminuria, as well as cardiac, aortic, and renal plasminogen activator inhibitor-1 mRNA expression during angiotensin II treatment. Mineralocorticoid receptor antagonism reduced angiotensin II/salt-induced glomerular hypertrophy, but aldosterone deficiency did not. Combined mineralocorticoid receptor antagonism and aldosterone deficiency reduced blood urea nitrogen and restored nephrin immunoreactivity. Angiotensin II/salt also promoted glomerular injury through the mineralocorticoid receptor in the absence of aldosterone. Thus, mineralocorticoid antagonism may have protective effects in the kidney beyond aldosterone synthase inhibition.

Figures

Figure 1
Figure 1
Systolic blood pressure (SBP) during regular chow (A) and spironolactone chow (B). Angiotensin (Ang) II increased SBP significantly in wild-type (WT) (○) and aldosterone synthase-deficient (As-/-) (▼) mice, but the blood pressure response was attenuated in As-/-. *P<0.05 vs. WT-vehicle; †P<0.05 vs. WT-Ang II.
Figure 2
Figure 2
Angiotensin (Ang) II increased cardiac mass (A) and caused cardiac interstitial fibrosis (B) and perivascular fibrosis (C) in wild-type (WT) mice. Cardiac hypertrophy was similarly abrogated in spironolactone (SPL)-treated and aldosterone synthase-deficient (As-/-) mice. Interstitial and perivascular fibrosis were attenuated and not significantly increased in SPL-treated WT mice and were prevented in aldosterone synthase-deficient (As-/-) mice. Representative images of cardiac perivascular fibrosis are shown for each treatment group (D); Masson-trichrome (400×), scale bar = 200μm. *P<0.05 vs. WT-vehicle; †P<0.05 vs. WT-Ang II.
Figure 3
Figure 3
Angiotensin (Ang) II increased aortic intima-media thickness (A) and adventitial thickness (B) in vehicle-treated wild-type (WT), but not in spironolactone (SPL)-treated or aldosterone synthase-deficient (As-/-) mice. Representative images are provided (C); Masson- trichrome stain (400×), scale bar =100μm. *P<0.05 vs. WT-vehicle, †P<0.05 vs. WT-Ang II.
Figure 4
Figure 4
Angiotensin (Ang) II caused an increase in BUN (A), albuminuria (B), and glomerular enlargement (C) in wild-type (WT) mice, and BUN elevation and glomerular enlargement in aldosterone synthase-deficient (As-/-) mice. Only combined spironolactone and genetic aldosterone deficiency reduced Ang II-induced BUN elevation. Spironolactone (SPL) prevented albuminuria in Ang II-treated WT mice. As-/- mice were also protected against Ang II-induced albuminuria. SPL prevented glomerular expansion, whereas aldosterone synthase deficiency did not. *P<0.05 vs. WT-vehicle; †P<0.01 vs. WT-Ang II; ‡P<0.05 vs. As-/--Vehicle; □P<0.05 vs. WT-Ang II-SPL; §P<0.05 vs. As-/--Ang II. BUN, blood urea nitrogen.
Figure 5
Figure 5
Representative images of kidney histologic injury are shown for each treatment group (A); Periodic Acid Schiff (PAS) stain. Angiotensin (Ang) II treatment decreased nephrin immunoreactivity (B) in wild-type (WT) and aldosterone synthase deficient (As-/-) mice. (400×), scale bars = 100μm.
Figure 6
Figure 6
Angiotensin (Ang) II treatment increased plasminogen activator inhibitor (Pai)-1 mRNA levels in cardiac (A), renal (B), and aortic (C) tissue in wild-type (WT) mice. Spironolactone (SPL) or genetic aldosterone synthase deficiency (As-/-) prevented this increase within the heart and aorta, and attenuated the effect within the kidney. *P<0.05 vs. WT-vehicle; †P<0.05 vs. WT-Ang II; ‡P<0.05 vs. As-/--Vehicle-SPL.

References

    1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–1462.
    1. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–1906.
    1. 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.
    1. 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.
    1. 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.
    1. Nagata K, Obata K, Xu J, et al. Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension. 2006;47:656–664.
    1. Nagase M, Shibata S, Yoshida S, et al. Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension. 2006;47:1084–1093.
    1. Du J, Fan YY, Hitomi H, et al. Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats. Am J Physiol Renal Physiol. 2009;297:F802–F808.
    1. Fiebeler A, Nussberger J, Shagdarsuren E, et al. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation. 2005;111:3087–3094.
    1. Lea WB, Kwak ES, Luther JM, et al. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int. 2009;75:936–944.
    1. Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res. 2005;96:643–650.
    1. Mazak I, Fiebeler A, Muller DN, et al. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004;109:2792–2800.
    1. Luther JM, Wang Z, Ma J, et al. Endogenous aldosterone contributes to acute angiotensin II-stimulated plasminogen activator inhibitor-1 and preproendothelin-1 expression in heart but not aorta. Endocrinology. 2009;150:2229–2236.
    1. Makhanova N, Lee G, Takahashi N, et al. Kidney function in mice lacking aldosterone. Am J Physiol Renal Physiol. 2006;290:F61–F69.
    1. Fiebeler A, Schmidt F, Muller DN, et al. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension. 2001;37:787–793.
    1. Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63:1791–1800.
    1. Rocha R, Martin-Berger CL, Yang P, et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology. 2002;143:4828–4836.
    1. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol. 1993;25:563–575.
    1. Young M, Funder JW. Eplerenone, but not steroid withdrawal, reverses cardiac fibrosis in deoxycorticosterone/salt-treated rats. Endocrinology. 2004;145:3153–3157.
    1. Neves MF, Amiri F, Virdis A, et al. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol. 2005;83:999–1006.
    1. Funder JW. Mineralocorticoid receptors and cardiovascular damage: it's not just aldosterone. Hypertension. 2006;47:634–635.
    1. Wang H, Shimosawa T, Matsui H, et al. Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. J Hypertens. 2008;26:1453–1462.
    1. Mulder P, Mellin V, Favre J, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone. Eur Heart J. 2008;29:2171–2179.
    1. Matsui Y, Jia N, Okamoto H, et al. Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension. 2004;43:1195–1201.
    1. Rocha R, Stier CT, Jr., Kifor I, et al. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000;141:3871–3878.
    1. Gomez-Sanchez EP, Gomez-Sanchez CM, Plonczynski M, Gomez-Sanchez CE. Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension. Exp Physiol. 2010;95:120–130.
    1. 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.
    1. Fujita T. Mineralocorticoid receptors, salt-sensitive hypertension, and metabolic syndrome. Hypertension. 2010;55:813–818.
    1. Grossmann C, Gekle M. New aspects of rapid aldosterone signaling. Mol Cell Endocrinol. 2009;308:53–62.
    1. Rafiq K, Nakano D, Ihara G, et al. Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats. J Hypertens. 2011;29:290–298.
    1. Brem AS, Morris DJ, Ge Y, et al. Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11β-HSD activity. American Journal of Physiology Renal Physiology. 2010;298:F1178–F1187.
    1. Lee SH, Yoo TH, Nam BY, et al. Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions. Am J Physiol Renal Physiol. 2009;297:F1381–F1390.
    1. Terada Y, Kobayashi T, Kuwana H, et al. Aldosterone stimulates proliferation of mesangial cells by activating mitogen-activated protein kinase 1/2, cyclin D1, and cyclin A. J Am Soc Nephrol. 2005;16:2296–2305.
    1. Rautureau Y, Paradis P, Schiffrin EL. Cross-talk between aldosterone and angiotensin signaling in vascular smooth muscle cells. Steroids. 2011
    1. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl. 2005:S57–S65.
    1. Eddy AA, Fogo AB. Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol. 2006;17:2999–3012.
    1. Hollenberg NK. Implications of species difference for clinical investigation: studies on the renin-angiotensin system. Hypertension. 2000;35:150–154.
    1. Lee G, Makhanova N, Caron K, et al. Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice. Endocrinology. 2005;146:2650–2656.
    1. Weisberg AD, Albornoz F, Griffin JP, et al. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol. 2005;25:365–371.
    1. Quaschning T, Ruschitzka F, Shaw S, Luscher TF. Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. Hypertension. 2001;37:801–805.
    1. Ma J, Weisberg A, Griffin JP, et al. Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 2006;69:1064–1072.
    1. Dunn SR, Qi Z, Bottinger EP, et al. Utility of endogenous creatinine clearance as a measure of renal function in mice. Kidney Int. 2004;65:1959–1967.
    1. Collins TJ. ImageJ for microscopy. Biotechniques. 2007;43:25–30.
    1. Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-ΔΔCT Method. Methods. 2001;25:402–408.
    1. R Development Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; Vienna, Austria: 2010.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere