Advertisement

Role of Aldosterone in Renal Fibrosis

  • Aanchal Shrestha
  • Ruo-Chen Che
  • Ai-Hua ZhangEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)

Abstract

Aldosterone is a mineralocorticoid hormone, as its main renal effect has been considered as electrolyte and water homeostasis in the distal tubule, thus maintaining blood pressure and extracellular fluid homeostasis through the activation of mineralocorticoid receptor (MR) in epithelial cells. However, over the past decade, numerous studies have documented the significant role of aldosterone in the progression of chronic kidney disease (CKD) which has become a subject of interest. It is being studied that aldosterone can affect cardiovascular and renal system, thereby contributing to tissue inflammation, injury, glomerulosclerosis, and interstitial fibrosis. Aldosterone acts on renal vessels, renal cells (glomerular mesangial cells, podocytes, vascular smooth muscle cells, tubular epithelial cells, and interstitial fibroblasts), and infiltrating inflammatory cells, inducing reactive oxygen species (ROS) production, upregulated epithelial growth factor receptor (EGFR), and type 1 angiotensin (AT1) receptor expressions, and activating nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and EGFR to further promote cell proliferation, apoptosis, and proliferation. Phenotypic transformation of epithelial cells stimulates the expression of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), osteopontin (OPN), and plasminogen activator inhibitor-1 (PAI-1), eventually leading to renal fibrosis. MR antagonisms are related to inhibition of aldosterone-mediated pro-inflammatory and pro-fibrotic effect. In this review, we will summarize the important role of aldosterone in the pathogenesis of renal injury and fibrosis, emphasizing on its multiple underlying mechanisms and advances in aldosterone research along with the potential therapeutics for targeting MR in a renal fibrosis.

Keywords

Aldosterone Renal fibrosis Chronic kidney disease 

Notes

Acknowledgement and Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Abboud HE (2012) Mesangial cell biology. Exp Cell Res 318:979–985PubMedCrossRefGoogle Scholar
  2. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119:1438–1449PubMedPubMedCentralCrossRefGoogle Scholar
  3. Arima S, Kohagura K, Xu H-L, Sugawara A, Abe T, Satoh F et al (2003) Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol 14:2255–2263PubMedCrossRefGoogle Scholar
  4. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE et al (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237:268–275PubMedCrossRefGoogle Scholar
  5. Azizi M, Amar L, Menard J (2012) Aldosterone synthase inhibition in humans. Nephrol Dial Transplant 28:36–43PubMedCrossRefGoogle Scholar
  6. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappaB in the immune system. Annu Rev Immunol 12:141–179PubMedCrossRefGoogle Scholar
  7. Bai M, Chen Y, Zhao M, Zhang Y, He JC-J, Huang S et al (2017) NLRP3 inflammasome activation contributes to aldosterone-induced podocyte injury. Am J Physiol Renal Physiol 312:F556–F564PubMedCrossRefGoogle Scholar
  8. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H et al (2015) Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 314:884–894PubMedCrossRefGoogle Scholar
  9. Bianchi S, Bigazzi R, Campese VM (2006) Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 70:2116–2123PubMedCrossRefGoogle Scholar
  10. Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, McMahon EG (2003) Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int 63:1791–1800PubMedCrossRefGoogle Scholar
  11. Boldyreff B, Wehling M (2003) Non-genomic actions of aldosterone: mechanisms and consequences in kidney cells. Nephrol Dial Transplant 18:1693–1695PubMedCrossRefGoogle Scholar
  12. Bomback AS, Klemmer PJ (2007) The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 3:486–492PubMedCrossRefGoogle Scholar
  13. Bonvalet J, Alfaidy N, Farman N, Lombes M (1995) Aldosterone: intracellular receptors in human heart. Eur Heart J 16:92–97PubMedCrossRefGoogle Scholar
  14. Brown NJ (2013) Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 9:459–469PubMedPubMedCentralCrossRefGoogle Scholar
  15. Brown NJ, Kim KS, Chen YQ, Blevins LS, Nadeau JH, Meranze SG et al (2000a) Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab 85:336–344PubMedGoogle Scholar
  16. Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M et al (2000b) Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 58:1219–1227PubMedCrossRefGoogle Scholar
  17. Brunskill EW, Potter SS (2012) Changes in the gene expression programs of renal mesangial cells during diabetic nephropathy. BMC Nephrol 13:70PubMedPubMedCentralCrossRefGoogle Scholar
  18. Burns W, Thomas M (2011) Angiotensin II and its role in tubular epithelial to mesenchymal transition associated with chronic kidney disease. Cells Tissues Organs 193:74–84PubMedCrossRefGoogle Scholar
  19. Chen C, Liang W, Jia J, Van Goor H, Singhal PC, Ding G (2009) Aldosterone induces apoptosis in rat podocytes: role of PI3-K/Akt and p38MAPK signaling pathways. Nephron Exp Nephrol 113:e26–e34PubMedPubMedCentralCrossRefGoogle Scholar
  20. Christ M, Wehling M (1999) Rapid actions of aldosterone: lymphocytes, vascular smooth muscle and endothelial cells. Steroids 64:35–41PubMedCrossRefGoogle Scholar
  21. Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ (2006) 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 1:256–262PubMedCrossRefGoogle Scholar
  22. Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Cabrini G et al (2001) Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol 37:1808–1812PubMedCrossRefGoogle Scholar
  23. Coirini H, Mari A, De Nicola AF, Rainbow TC, McEwen BS (1985) Further studies of brain aldosterone binding sites employing new mineralocorticoid and glucocorticoid receptor markers in vitro. Brain Res 361:212–216PubMedCrossRefGoogle Scholar
  24. Conn JW, Knopf RF, Nesbit RM (1964) Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107:159–172PubMedCrossRefGoogle Scholar
  25. Ding W, Yang L, Zhang M, Gu Y (2012) Chronic inhibition of nuclear factor kappa B attenuates aldosterone/salt-induced renal injury. Life Sci 90:600–666PubMedCrossRefGoogle Scholar
  26. Epstein M (2006) Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med 119:912–919PubMedCrossRefGoogle Scholar
  27. Farman N, Rafestin-Oblin M-E (2001) Multiple aspects of mineralocorticoid selectivity. Am J Physiol Renal Physiol 280:F181–F192PubMedCrossRefGoogle Scholar
  28. Forrester SJ, Kawai T, O’Brien S, Thomas W, Harris RC, Eguchi S (2016) Epidermal growth factor receptor transactivation: mechanisms, pathophysiology, and potential therapies in the cardiovascular system. Annu Rev Pharmacol Toxicol 56:627–653PubMedCrossRefGoogle Scholar
  29. Funder J, Myles K (1996) Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies. Endocrinology 137:5264–5268PubMedCrossRefGoogle Scholar
  30. Funder JW (2010) Aldosterone and mineralocorticoid receptors in the cardiovascular system. Prog Cardiovasc Dis 52:393–400PubMedCrossRefGoogle Scholar
  31. Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242:583–585PubMedCrossRefPubMedCentralGoogle Scholar
  32. Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N et al (2008) Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res 31:59–67PubMedCrossRefGoogle Scholar
  33. Gauer S, Segitz V, Goppelt-Struebe M (2007) Aldosterone induces CTGF in mesangial cells by activation of the glucocorticoid receptor. Nephrol Dial Transplant 22:3154–3159PubMedCrossRefPubMedCentralGoogle Scholar
  34. Gonzalez A, López B, Dı́ez J (2004) Fibrosis in hypertensive heart disease: role of the renin-angiotensin-aldosterone system. Med Clin North Am 88:83–97PubMedCrossRefGoogle Scholar
  35. Greene E, Kren S, Hostetter T (1996) Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 98:1063–1068PubMedPubMedCentralCrossRefGoogle Scholar
  36. Gros R, Ding Q, Sklar LA, Prossnitz EE, Arterburn JB, Chorazyczewski J et al (2011) GPR30 expression is required for the mineralocorticoid receptor–independent rapid vascular effects of aldosterone. Hypertension 57:442–451PubMedPubMedCentralCrossRefGoogle Scholar
  37. Gros R, Ding Q, Liu B, Chorazyczewski J, Feldman RD (2013) Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation. Am J Physiol Cell Physiol 304:C532–C540PubMedCrossRefPubMedCentralGoogle Scholar
  38. Grossmann C, Krug AW, Freudinger R, Mildenberger S, Voelker K, Gekle M (2007) Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter. Am J Physiol Endocrinol Metab 292:E1790–E1800PubMedCrossRefGoogle Scholar
  39. Han K, Kang Y, Han SY, Jee Y, Lee M, Han J et al (2006) Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats. Kidney Int 70:111–120PubMedCrossRefPubMedCentralGoogle Scholar
  40. Han JS, Choi BS, Yang CW, Kim YS (2009) Aldosterone-induced TGF-β1 expression is regulated by mitogen-activated protein kinases and activator protein-1 in mesangial cells. J Korean Med Sci 24:S195–S203PubMedPubMedCentralCrossRefGoogle Scholar
  41. Han HI, Skvarca LB, Espiritu EB, Davidson AJ, Hukriede NA (2019) The role of macrophages during acute kidney injury: destruction and repair. Pediatr Nephrol 34:1–9CrossRefGoogle Scholar
  42. Hao J, Ren L, Zhang L, Kong D, Hao L (2015) Aldosterone-induced inflammatory response of mesangial cells via angiotension II receptors. J Renin Angiotensin Aldosterone Syst 16:739–748PubMedCrossRefGoogle Scholar
  43. Heber S, Denk L, Hu K, Minuth WW (2007) Modulating the development of renal tubules growing in serum-free culture medium at an artificial interstitium. Tissue Eng 13:281–292PubMedCrossRefGoogle Scholar
  44. Hostetter TH, Ibrahim HN (2003) Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol 14:2395–2401PubMedCrossRefGoogle Scholar
  45. Huang W, Xu C, Kahng KW, Noble NA, Border WA, Huang Y (2008) Aldosterone and TGF-β1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells. Am J Physiol Renal Physiol 294:F1287–F1295PubMedCrossRefGoogle Scholar
  46. Huang S, Zhang A, Ding G, Chen R (2009) Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am J Physiol Renal Physiol 296:F1323–F1333PubMedCrossRefGoogle Scholar
  47. Huang L, Nikolic-Paterson D, Ma F, Tesch G (2012) Aldosterone induces kidney fibroblast proliferation via activation of growth factor receptors and PI3K/MAPK signalling. Nephron Exp Nephrol 120:e115–e122PubMedCrossRefPubMedCentralGoogle Scholar
  48. Ikeda H, Tsuruya K, Toyonaga J, Masutani K, Hayashida H, Hirakata H et al (2009) Spironolactone suppresses inflammation and prevents L-NAME–induced renal injury in rats. Kidney Int 75:147–155PubMedCrossRefGoogle Scholar
  49. Irita J, Okura T, Kurata M, Miyoshi K-i, Fukuoka T, Higaki J (2008) Osteopontin in rat renal fibroblasts: functional properties and transcriptional regulation by aldosterone. Hypertension 51:507–513PubMedCrossRefPubMedCentralGoogle Scholar
  50. Jaisser F, Farman N (2016) Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol Rev 68:49–75PubMedCrossRefGoogle Scholar
  51. Juknevicius I, Segal Y, Kren S, Lee R, Hostetter TH (2004) Effect of aldosterone on renal transforming growth factor-β. Am J Physiol Renal Physiol 286:F1059–F1062PubMedCrossRefGoogle Scholar
  52. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kiyomoto H, Rafiq K, Mostofa M, Nishiyama A (2008) Possible underlying mechanisms responsible for aldosterone and mineralocorticoid receptor-dependent renal injury. J Pharmacol Sci 108:399–405PubMedCrossRefGoogle Scholar
  54. Kolkhof P, Borden SA (2012) Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol 350:310–317PubMedCrossRefGoogle Scholar
  55. Kornel L (1994) Colocalization of 11β-hydroxysteroid dehydrogenase and mineralocorticoid receptors in cultured vascular smooth muscle cells. Am J Hypertens 7:100–103PubMedCrossRefGoogle Scholar
  56. Lenzini L, Seccia TM, Aldighieri E, Belloni AS, Bernante P, Giuliani L et al (2007) Heterogeneity of aldosterone-producing adenomas revealed by a whole transcriptome analysis. Hypertension 50:1106–1113PubMedCrossRefGoogle Scholar
  57. Li C, Ding XY, Xiang DM, Xu J, Huang XL, Hou FF et al (2015) Enhanced M1 and impaired M2 macrophage polarization and reduced mitochondrial biogenesis via inhibition of AMP kinase in chronic kidney disease. Cell Physiol Biochem 36:358–372PubMedCrossRefGoogle Scholar
  58. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696PubMedPubMedCentralCrossRefGoogle Scholar
  59. Martín-Fernández B, Rubio-Navarro A, Cortegano I, Ballesteros S, Alía M, Cannata-Ortiz P et al (2016) Aldosterone induces renal fibrosis and inflammatory M1-macrophage subtype via mineralocorticoid receptor in rats. PLoS ONE 11:e0145946PubMedPubMedCentralCrossRefGoogle Scholar
  60. Mathew JT, Patni H, Chaudhary AN, Liang W, Gupta A, Chander PN et al (2008) Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol 295:F73–F81PubMedPubMedCentralCrossRefGoogle Scholar
  61. Mihailidou AS, Funder JW (2005) Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system. Steroids 70:347–351PubMedCrossRefGoogle Scholar
  62. Min LJ, Mogi M, Li JM, Iwanami J, Iwai M, Horiuchi M (2005) Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res 97:434–442PubMedCrossRefGoogle Scholar
  63. Minuth WW, Denk L, Heber S (2005) Growth of embryonic renal parenchyme at the interphase of a polyester artificial interstitium. Biomaterials 26:6588–6598PubMedCrossRefGoogle Scholar
  64. Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP et al (2005) Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol 16:2906–2912PubMedCrossRefGoogle Scholar
  65. Morgado-Pascual JL, Rayego-Mateos S, Valdivielso JM, Ortiz A, Egido J, Ruiz-Ortega M (2015) Paricalcitol inhibits aldosterone-induced proinflammatory factors by modulating epidermal growth factor receptor pathway in cultured tubular epithelial cells. Biomed Res Int 2015:783538PubMedPubMedCentralCrossRefGoogle Scholar
  66. 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
  67. 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
  68. Naruse M, Tanabe A, Sato A, Takagi S, Tsuchiya K, Imaki T et al (2002) Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 40(1):28–33PubMedCrossRefGoogle Scholar
  69. Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S et al (2004) Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension 43:841–848PubMedCrossRefGoogle Scholar
  70. Nishiyama A, Yao L, Fan Y, Kyaw M, Kataoka N, Hashimoto K et al (2005) Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability. Hypertension 45:710–716PubMedCrossRefGoogle Scholar
  71. Nishiyama A, Kobori H, Konishi Y, Morikawa T, Maeda I, Okumura M et al (2010) Mineralocorticoid receptor blockade enhances the antiproteinuric effect of an angiotensin II blocker through inhibiting podocyte injury in type 2 diabetic rats. J Pharmacol Exp Ther 332:1072–1080PubMedPubMedCentralCrossRefGoogle Scholar
  72. Pavenstadt H, Kriz W, Kretzler M (2003) Cell biology of the glomerular podocyte. Physiol Rev 83:253–307PubMedCrossRefGoogle Scholar
  73. Phanish MK, Winn S, Dockrell M (2010) Connective tissue growth factor-(CTGF, CCN2)–a marker, mediator and therapeutic target for renal fibrosis. Nephron Exp Nephrol 114:e83–e92PubMedCrossRefGoogle Scholar
  74. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709–717PubMedCrossRefGoogle Scholar
  75. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R (2008) Serum potassium and clinical outcomes in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS). Circulation 118:1643–1650PubMedCrossRefGoogle Scholar
  76. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H et al (2013) Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 34:2453–2463PubMedPubMedCentralCrossRefGoogle Scholar
  77. Porter GA, Edelman IS (1964) The action of aldosterone and related corticosteroids on sodium transport across the toad bladder. J Clin Invest 43:611–620PubMedPubMedCentralCrossRefGoogle Scholar
  78. Porter GA, Bogoroch R, Edelman IS (1964) On the mechanism of action of aldosterone on sodium transport: the role of RNA synthesis. Proc Natl Acad Sci U S A 52:1326–1333PubMedPubMedCentralCrossRefGoogle Scholar
  79. Rogerson FM, Fuller PJ (2000) Mineralocorticoid action. Steroids 65:61–73PubMedCrossRefGoogle Scholar
  80. Rüster C, Wolf G (2006) Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 17:2985–2991PubMedCrossRefGoogle Scholar
  81. Sato A, Fukuda S (2013) Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist. Hypertens Res 36:879–884PubMedCrossRefGoogle Scholar
  82. Schjoedt K, Andersen S, Rossing P, Tarnow L, Parving H-H (2004) Aldosterone escape during blockade of the renin–angiotensin–aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 47:1936–1939PubMedCrossRefGoogle Scholar
  83. Schjoedt K, Rossing K, Juhl T, Boomsma F, Tarnow L, Rossing P et al (2006) Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 70:536–542PubMedCrossRefGoogle Scholar
  84. Shankland S (2006) The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 69:2131–2147PubMedCrossRefGoogle Scholar
  85. Sheng L, Yang M, Ding W, Zhang M, Niu J, Qiao Z et al (2016) Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney. Exp Cell Res 346:99–110PubMedCrossRefGoogle Scholar
  86. 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
  87. Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H et al (2008) Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 14:1370–1376PubMedCrossRefGoogle Scholar
  88. Simpson S (1953) Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism. Experientia 9(333–335):3Google Scholar
  89. Spat A, Hunyady L (2004) Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev 84:489–539PubMedCrossRefGoogle Scholar
  90. Su M, Dhoopun A-R, Yuan Y, Huang S, Zhu C, Ding G et al (2013) Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury. Am J Physiol Renal Physiol 305:F520–F531PubMedCrossRefGoogle Scholar
  91. Sun Y, Zhang J, Zhang JQ, Ramires FJ (2000) Local angiotensin II and transforming growth factor-β1 in renal fibrosis of rats. Hypertension 35:1078–1084PubMedCrossRefGoogle Scholar
  92. Terada Y, Ueda S, Hamada K, Shimamura Y, Ogata K, Inoue K et al (2012) Aldosterone stimulates nuclear factor-kappa B activity and transcription of intercellular adhesion molecule-1 and connective tissue growth factor in rat mesangial cells via serum-and glucocorticoid-inducible protein kinase-1. Clin Exp Nephrol 16:81–88PubMedCrossRefGoogle Scholar
  93. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  94. Trachtman H, Weiser AC, Valderrama E, Morgado M, Palmer LS (2004) Prevention of renal fibrosis by spironolactone in mice with complete unilateral ureteral obstruction. J Urol 172:1590–1594PubMedCrossRefGoogle Scholar
  95. Unger T, Paulis L, Sica DA (2011) Therapeutic perspectives in hypertension: novel means for renin–angiotensin–aldosterone system modulation and emerging device-based approaches. Eur Heart J 32:2739–2747PubMedPubMedCentralCrossRefGoogle Scholar
  96. Urata H, Hoffmann S, Ganten D (1994a) Tissue angiotensin II system in the human heart. Eur Heart J 15:68–78PubMedCrossRefGoogle Scholar
  97. Urata H, Strobel F, Ganten D (1994b) Widespread tissue distribution of human chymase. J Hypertens Suppl 12:S17–S22PubMedGoogle Scholar
  98. Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A et al (2016) Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1459–1544CrossRefGoogle Scholar
  99. Weldon SM, Cerny MA, Gueneva-Boucheva K, Cogan D, Guo X, Moss N et al (2016) Selectivity of BI 689648, a novel, highly selective aldosterone synthase inhibitor: comparison with FAD286 and LCI699 in nonhuman primates. J Pharmacol Exp Ther 359:142–150PubMedCrossRefGoogle Scholar
  100. Williams GH (2005) Aldosterone biosynthesis, regulation, and classical mechanism of action. Heart Fail Rev 10:7–13PubMedCrossRefGoogle Scholar
  101. Williams JS, Williams GH (2003) 50th anniversary of aldosterone. J Clin Endocrinol Metab 88:2364–2372PubMedCrossRefGoogle Scholar
  102. Wolf G, Chen S, Ziyadeh FN (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54:1626–1634PubMedCrossRefGoogle Scholar
  103. Yamada M, Kushibiki M, Osanai T, Tomita H, Okumura K (2008) Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization. Cardiovasc Res 79:169–178PubMedCrossRefGoogle Scholar
  104. Yuan J, Jia R, Bao Y (2007) Aldosterone up-regulates production of plasminogen activator inhibitor-1 by renal mesangial cells. J Biochem Mol Biol 40:180–188PubMedGoogle Scholar
  105. Yuan Y, Huang S, Wang W, Wang Y, Zhang P, Zhu C et al (2012a) Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury. Kidney Int 82:771–789PubMedCrossRefGoogle Scholar
  106. Yuan Y, Chen Y, Zhang P, Huang S, Zhu C, Ding G et al (2012b) Mitochondrial dysfunction accounts for aldosterone-induced epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells. Free Radic Biol Med 53:30–43PubMedCrossRefGoogle Scholar
  107. Yuan Y, Zhang A, Qi J, Wang H, Liu X, Zhao M et al (2017) P53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction. Am J Physiol Renal Physiol 314:F798–F808PubMedCrossRefGoogle Scholar
  108. Zhang A, Jia Z, Guo X, Yang T (2007) Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin. Am J Physiol Renal Physiol 293:F723–F731PubMedCrossRefGoogle Scholar
  109. Zhang A, Jia Z, Wang N, Tidwell TJ, Yang T (2011) Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice. Kidney Int 80:51–60PubMedCrossRefGoogle Scholar
  110. Zhang A, Han Y, Wang B, Li S, Gan W (2015) Beyond gap junction channel function: the expression of Cx43 contributes to aldosterone-induced mesangial cell proliferation via the ERK1/2 and PKC pathways. Cell Physiol Biochem 36:1210–1222PubMedCrossRefGoogle Scholar
  111. Zhu C, Huang S, Yuan Y, Ding G, Chen R, Liu B et al (2011) Mitochondrial dysfunction mediates aldosterone-induced podocyte damage: a therapeutic target of PPARγ. Am J Pathol 178:2020–2031PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of NephrologyChildren’s Hospital of Nanjing Medical UniversityNanjingChina

Personalised recommendations