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Clinical and Experimental Nephrology

Erschienen in:

01.02.2014 | Review Article

Mineralocorticoid receptor activation as an etiological factor in kidney diseases

verfasst von: Kohei Ueda, Miki Nagase

Erschienen in: Clinical and Experimental Nephrology | Ausgabe 1/2014

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Abstract

The mineralocorticoid receptor (MR) is a member of the steroid-responsive nuclear receptor family. Currently, in addition to its classical role in fluid homeostasis, attention has been focused on the pro-proteinuric and pro-inflammatory effects of MR in renal and cardiovascular diseases. Since proteinuria has been shown to be an important factor in the prognosis of patients with chronic kidney disease (CKD) [according to the newest Japanese Society of Nephrology and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the treatment of CKD], it is worth discussing the role of MR in the progression of proteinuric CKD and the possible association with podocyte injury. Rac1, a Rho-GTPase family protein, is known for its role in the regulation of the cytoskeleton. We discovered the role of active Rac1 in amplifying MR activation in one of our studies and then continued to study how the Rac1−MR pathway contributes to the progression of kidney diseases. We then discovered the harmful effects of the activation of the Rac1−MR pathway in response to salt loading in the kidney for proteinuric kidney diseases of various animal models with salt-sensitive hypertension, such as Dahl salt-sensitive rats, RhoGDIα-knockout mice, angiotensin II-overproducing mice, and aldosterone-infused rats. In this review, we have introduced recent findings that suggest the contribution of MR activation to kidney diseases and the role of the Rac1−MR pathway in kidney injury associated with salt-sensitive hypertension and proteinuria. Thus, the Rac1−MR pathway is a potential therapeutic target in patients with proteinuric CKD.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO. Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2012;2013(3):1–150.

[Special issue: Clinical practice guidebook for diagnosis and treatment of chronic kidney disease 2012]. Nihon Jinzo Gakkai Shi. 2012;54(8):1034–191.

Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010; 375(9731):2073–81.

Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney Int. 2011;79(10):1051–60.PubMedCrossRef

Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, Ohkubo T, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet. 2012;380(9854):1649–61.PubMedCrossRef

Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet. 2012;380(9844):807–14.PubMedCrossRef

Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79(12):1331–40.PubMedCrossRef

Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80(1):93–104.PubMedCrossRef

Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–53.PubMedCrossRef

10.

Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.PubMedCrossRef

11.

Nagase M. Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome. Clin Exp Nephrol. 2010;14(4):303–14.PubMedCrossRef

12.

Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121(8):3233–43.PubMedCentralPubMedCrossRef

13.

Gomez-Sanchez CE, Warden M, Gomez-Sanchez MT, Hou X, Gomez-Sanchez EP. Diverse immunostaining patterns of mineralocorticoid receptor monoclonal antibodies. Steroids. 2011;76(14):1541–5.PubMedCentralPubMedCrossRef

14.

Rickard AJ, Morgan J, Tesch G, Funder JW, Fuller PJ, Young MJ. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension. 2009;54(3):537–43.PubMedCrossRef

15.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, 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(10):709–17.PubMedCrossRef

16.

Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–21.PubMedCrossRef

17.

Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology. 2006;147(11):5363–73.PubMedCrossRef

18.

Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17(5):1362–72.PubMedCrossRef

19.

Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension. 1998;31(1 Pt 2):451–8.PubMedCrossRef

20.

Blasi ER, Rocha R, Rudolph AE, Blomme EAG, Polly ML, Mcmahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63(5):1791–800.PubMedCrossRef

21.

Ikeda H, Tsuruya K, Toyonaga J, Masutani K, Hayashida H, Hirakata H, et al. Spironolactone suppresses inflammation and prevents L-NAME–induced renal injury in rats. Kidney Int. 2008;75(2):147–55.PubMedCrossRef

22.

Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, 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(12):3438–46.PubMedCrossRef

23.

Zitt E, Eller K, Huber JM, Kirsch AH, Tagwerker A, Mayer G, et al. The selective mineralocorticoid receptor antagonist eplerenone is protective in mild anti-GBM glomerulonephritis. Int J Clin Exp Pathol. 2011;4(6):606–15.PubMedCentralPubMed

24.

Asai M, Monkawa T, Marumo T, Fukuda S, Tsuji M, Yoshino J, et al. Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-Thy-1 irreversible nephritis. Hypertens Res. 2004;27(12):971–8.PubMedCrossRef

25.

Monrad SU, Killen PD, Anderson MR, Bradke A, Kaplan MJ. The role of aldosterone blockade in murine lupus nephritis. Arthritis Res Ther. 2008;10(1):R5.PubMedCentralPubMedCrossRef

26.

Fukuda A, Fujimoto S, Iwatsubo S, Kawachi H, Kitamura K. Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome. Nephrology. 2010;15(3):321–6.PubMedCrossRef

27.

Nakhoul F, Khankin E, Yaccob A, Kawachi H, Karram T, Awaad H, et al. Eplerenone potentiates the antiproteinuric effects of enalapril in experimental nephrotic syndrome. Am J Physiol Renal Physiol. 2008;294(3):F628–37.PubMedCrossRef

28.

Terada Y, Kuwana H, Kobayashi T, Okado T, Suzuki N, Yoshimoto T, et al. Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium. J Am Soc Nephrol. 2008;19(2):298–309.PubMedCrossRef

29.

Leroy V, De Seigneux S, Agassiz V, Hasler U, Rafestin-Oblin ME, Vinciguerra M, et al. Aldosterone activates NF-κB in the collecting duct. J Am Soc Nephrol. 2009;20(1):131–44.PubMedCrossRef

30.

D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365(25):2398–411.PubMedCrossRef

31.

Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74:299–323.PubMedCentralPubMedCrossRef

32.

Chen C, Liang W, Jia J, van Goor H, Singhal PC, Ding G. Aldosterone induces apoptosis in rat podocytes: role of PI3-K/Akt and p38MAPK signaling pathways. Nephron Exp Nephrol. 2009;113(1):e26–34.PubMedCrossRef

33.

Zhu C, Huang S, Yuan Y, Ding G, Chen R, Liu B, et al. Mitochondrial dysfunction mediates aldosterone-induced podocyte damage. Am J Pathol. 2011;178(5):2020–31.PubMedCrossRef

34.

Yuan Y, Huang S, Wang W, Wang Y, Zhang P, Zhu C, et al. Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury. Kidney Int. 2012;30:1–19.

35.

Ogawa Y, Mukoyama M, Yokoi H, Kasahara M, Mori K, Kato Y, et al. Natriuretic peptide receptor guanylyl cyclase-A protects podocytes from aldosterone-induced glomerular injury. J Am Soc Nephrol. 2012;23(7):1198–209.PubMedCrossRef

36.

Fakitsas P, Adam G, Daidié D, van Bemmelen MX, Fouladkou F, Patrignani A, et al. Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation. J Am Soc Nephrol. 2007;18(4):1084–92.PubMedCrossRef

37.

Toyonaga J, Tsuruya K, Ikeda H, Noguchi H, Yotsueda H, Fujisaki K, et al. Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production. Nephrol Dial Transplant. 2011;26(8):2475–84.PubMedCrossRef

38.

Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14(12):1370–6.PubMedCrossRef

39.

Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and SGK1. Hypertension. 2006;49(2):355–64.CrossRef

40.

Kawarazaki W, Nagase M, Yoshida S, Takeuchi M, Ishizawa K, Ayuzawa N, et al. Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. J Am Soc Nephrol. 2012;23(6):997–1007.PubMedCrossRef

41.

Kitada K, Nakano D, Liu Y, Fujisawa Y, Hitomi H, Shibayama Y, et al. Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats. PLoS One. 2012;7(7):e41896.PubMedCentralPubMedCrossRef

42.

Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59(2):500–6.PubMedCrossRef

43.

Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59(3):251–87.PubMedCentralPubMedCrossRef

44.

Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al-Saadi N, et al. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation. 2005;111(23):3087–94.PubMedCrossRef

45.

Lea WB, Kwak ES, Luther JM, Fowler SM, Wang Z, Ma J, et al. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int. 2009;75(9):936–44.PubMedCentralPubMedCrossRef

46.

Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542–51.PubMedCrossRef

47.

Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1:940–51.PubMedCrossRef

48.

van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens. 2006;24(11):2285–92.PubMedCrossRef

49.

Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006;70(12):2116–23.PubMed

50.

Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol. 2006;1(2):256–62.PubMedCrossRef

51.

Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641–50.PubMedCrossRef

52.

Nagai Y, Miyata K, Sun GP, Rahman M, Kimura S, Miyatake A, et al. Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in rat renal fibroblasts. Hypertension. 2005;46(4):1039–45.PubMedCrossRef

53.

Nishiyama A, Yao L, Fan Y, Kyaw M, Kataoka N, Hashimoto K, et al. Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability. Hypertension. 2005;45(4):710–6.PubMedCrossRef

54.

Jeong Y, Chaupin DF, Matsushita K, Yamakuchi M, Cameron SJ, Morrell CN, et al. Aldosterone activates endothelial exocytosis. Proc Natl Acad Sci USA. 2009;106(10):3782–7.PubMedCrossRef

55.

McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012;18(9):1429–33.PubMedCentralPubMedCrossRef

56.

Barish GD, Downes M, Alaynick WA, Yu RT, Ocampo CB, Bookout AL, et al. A nuclear receptor atlas: macrophage activation. Mol Endocrinol. 2005;19(10):2466–77.PubMedCrossRef

57.

Bienvenu LA, Morgan J, Rickard AJ, Tesch GH, Cranston GA, Fletcher EK, et al. Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis. Endocrinology. 2012;153(7):3416–25.PubMedCrossRef

Titel: Mineralocorticoid receptor activation as an etiological factor in kidney diseases
verfasst von: Kohei Ueda
Miki Nagase
Publikationsdatum: 01.02.2014
Verlag: Springer Japan
Erschienen in: Clinical and Experimental Nephrology / Ausgabe 1/2014
Print ISSN: 1342-1751
Elektronische ISSN: 1437-7799
DOI: https://doi.org/10.1007/s10157-013-0827-3

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