Skip to main content

Advertisement

SpringerLink
Log in

Genomic and rapid effects of aldosterone: what we know and do not know thus far

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor—the “unknown receptor”—is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

11β-HSD1:

11β-Hydroxysteroid dehydrogenase type 1

11β-HSD2:

11β-Hydroxysteroid dehydrogenase type 2

ACE1:

Angiotensin-converting enzyme type 1

ACE2:

Angiotensin-converting enzyme type 2

ACTH:

Adrenocorticotropic hormone

ADIPOQ:

Adiponectin gene

AKAP:

A-kinase anchoring protein

AMI:

Acute myocardium infraction

Ang II:

Angiotensin II

ANP:

Atrial natriuretic peptide

AP-1:

Activating protein-1

ASK1:

Protein apoptosis signal-regulating kinase 1

AT1:

Angiotensin receptor type I

BMK1:

Big MAP kinase 1

BNP, Brain-type natriuretic peptide

NT-proBNP:

N-terminal pro b-type natriuretic peptide

BR-4628:

MR antagonist

CaM:

Calcium/calmodulin

CaMKII:

Calmodulin-dependent protein kinase II

CNS:

Central nervous system

CTGF:

Connective tissue growth factor

CYP11B2:

Aldosterone synthase

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EIPA:

Ethylisopropylamiloride

ENaC:

Epithelial sodium channel

ERK5:

Extracellular signal-regulated kinase 5

ERK1/2:

Extracellular signal-regulated kinase 1 and 2

G36:

GPER-1 antagonist

G6PD:

Glucose-6-phosphate dehydrogenase

GPER-1:

G protein-coupled estrogen receptor-1

GPR30:

G protein-coupled receptor 30

GR:

Glucocorticoid receptor

HKC11:

Human kidney proximal tubule cells

ICAM-1:

Intercellular adhesion molecule-1

IP3:

Inositol triphosphate

IR:

Ischemia reperfusion

LOX:

Lipoxygenase

LV:

Left ventricle

M1-CCD:

M1 cortical collecting duct

MDCK:

Madin-Darby canine kidney cells

miR21:

MicroRNA-21

MR:

Mineralocorticoid receptor

MTAL:

Medullary thick ascending limb

Na+/Cl−:

Sodium-chloride symporter

Na+/K+ ATPase:

Sodium-potassium adenosine triphosphatase

NADPH:

Nicotinamide adenine dinucleotide phosphate

NBC:

Na+/HCO3− cotransporter

NBCe1:

Na+/HCO3−cotransporter electrogenic

NF-κB:

Nuclear factor kappa B

NHE:

Sodium-hydrogen antiporters

NO:

Nitric oxide

Nox2:

Nitric oxide synthase 2

PAI-1:

Plasminogen activator inhibitor-1

PEPCK:

Phosphoenolpyruvate carboxykinase gene

PI3K:

Phosphoinositide 3-kinase

PKA:

Protein kinase A

PKC:

Protein kinase C

PLC:

Phospholipase C

PLIN:

Perilipin gene

PPARΓ:

Receptors activated by peroxisome proliferator

RAAS:

Renin-angiotensin-aldosterone

Rac1:

A small signaling G protein

Ras:

A G protein or a guanosine nucleotide-binding protein

RhoA:

Ras homolog gene family member A

ROS:

Reactive oxygen specie

SGK-1:

Serine/threonine-protein kinase

SHRs:

Spontaneously hypertensive rats

STEMI:

ST Segment elevation myocardial infarction

STN:

Solitary tract nucleus

VSMCs:

Vascular smooth muscle cells

References

  1. Simpson SA, Tait JF, Wettstein A, Neher R, Von Euw J, Schindler O, Reichstein T (1954) Constitution of aldosterone, a new mineralocorticoid. Experientia 10(3):132–133

    Article  CAS  PubMed  Google Scholar 

  2. Dooley R, Harvey BJ, Thomas W (2012) Non-genomic actions of aldosterone: from receptors and signals to membrane targets. Mol Cell Endocrinol 350(2):223–234. doi:10.1016/j.mce.2011.07.019

    Article  CAS  PubMed  Google Scholar 

  3. Marver D, Kokko JP (1983) Renal target sites and the mechanism of action of aldosterone. Miner Electrolyte Metab 9(1):1–18

    CAS  PubMed  Google Scholar 

  4. Connell JM, Davies E (2005) The new biology of aldosterone. J Endocrinol 186(1):1–20. doi:10.1677/joe.1.06017

    Article  CAS  PubMed  Google Scholar 

  5. Boulkroun S, Fernandes-Rosa FL, Zennaro MC (2015) Molecular and cellular mechanisms of aldosterone producing adenoma development. Front Endocrinol (Lausanne) 6:95. doi:10.3389/fendo.2015.00095

    Google Scholar 

  6. Atlas SA (2007) The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 13(8 Suppl B):9–20

    PubMed  Google Scholar 

  7. Hermidorff MM, Faria Gde O, Amancio Gde C, de Assis LVM, Isoldi MC (2015) Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways? Biochem Cell Biol 93(1):83–93. doi:10.1139/bcb-2014-0110

    Article  CAS  PubMed  Google Scholar 

  8. Rao MS (2010) Inhibition of the renin angiotensin aldosterone system: focus on aliskiren. J Assoc Physicians India 58:102–108

    PubMed  Google Scholar 

  9. Zaman MA, Oparil S, Calhoun DA (2002) Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 1(8):621–636

    Article  CAS  PubMed  Google Scholar 

  10. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348(14):1309–1321. doi:10.1056/NEJMoa030207

    Article  CAS  PubMed  Google Scholar 

  11. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341(10):709–717. doi:10.1056/NEJM199909023411001

    Article  CAS  PubMed  Google Scholar 

  12. Hermidorff MM, de Assis LVM, Isoldi MC (2015) Antagonists of the mineralocorticoid receptor or a new pharmacological class? J Cell Sci Ther 2015(6):1–2. doi:10.4172/2157-7013.1000222

    Google Scholar 

  13. Araujo CM, Hermidorff MM, Amancio GCS, Lemos DS, Silva ME, de Assis LVM, Isoldi MC (2015) Rapid effects of aldosterone in primary cultures of cardiomyocytes—do they suggest the existence of a membrane-bound receptor? J Recept Signal Transduct Res:1–10. doi:10.3109/10799893.2015.1122042

  14. Porter GA, Edelman IS (1964) The action of aldosterone and related corticosteroids on sodium transport across the toad bladder. J Clin Investig 43(4):611–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marver D, Stewart J, Funder JW, Feldman D, Edelman IS (1974) Renal aldosterone receptors: studies with (3H)aldosterone and the anti-mineralocorticoid (3H)spirolactone (SC-26304). Proc Natl Acad Sci U S A 71(4):1431–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yang J, Chang CY, Safi R, Morgan J, McDonnell DP, Fuller PJ, Clyne CD, Young MJ (2011) Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Mol Endocrinol 25(1):32–43. doi:10.1210/me.2010-0193

    Article  PubMed  CAS  Google Scholar 

  17. Funder JW, Feldman D, Edelman IS (1972) Specific aldosterone binding in rat kidney and parotid. J Steroid Biochem 3(2):209–218

    Article  CAS  PubMed  Google Scholar 

  18. O’Malley B (2008) The year in basic science: nuclear receptors and coregulators. Mol Endocrinol 22(12):2751–2758. doi:10.1210/me.2008-0297

    Article  PubMed  CAS  Google Scholar 

  19. Dorrance AM (2014) Interfering with mineralocorticoid receptor activation: the past, present, and future. F1000Prime Rep 6:61. doi:10.12703/P6-61

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Funder JW (2007) Why are mineralocorticoid receptors so nonselective? Curr Hypertens Rep 9(2):112–116

    Article  CAS  PubMed  Google Scholar 

  21. Myles K, Funder JW (1996) Progesterone binding to mineralocorticoid receptors: in vitro and in vivo studies. Am J Phys 270(4 Pt 1):E601–E607

    CAS  Google Scholar 

  22. Quinkler M, Diederich S, Bahr V, Oelkers W (2004) The role of progesterone metabolism and androgen synthesis in renal blood pressure regulation. Horm Metab Res 36(6):381–386. doi:10.1055/s-2004-814572

    Article  CAS  PubMed  Google Scholar 

  23. Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombès M (2007) The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal 5:e012. doi:10.1621/nrs.05012

    PubMed  PubMed Central  Google Scholar 

  24. Kolkhof P, Jaisser F, Kim SY, Filippatos G, Nowack C, Pitt B (2016) Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol. doi:10.1007/164_2016_76

    PubMed  Google Scholar 

  25. Boldyreff B, Wehling M (2004) Aldosterone: refreshing a slow hormone by swift action. News Physiol Sci 19:97–100

    CAS  PubMed  Google Scholar 

  26. Verhovez A, Williams AT, Monticone S, Crudo V, Burrello J, Galmozzi M, Covella M, Veglio F, Mulatero P (2012) Genomic and non-genomic effects of aldosterone. Curr Signal Transduct Ther 7(2):132–141. doi:10.2174/157436212800376708

    Article  CAS  Google Scholar 

  27. Bhargava A, Fullerton MJ, Myles K, Purdy TM, Funder JW, Pearce D, Cole TJ (2001) The serum- and glucocorticoid-induced kinase is a physiological mediator of aldosterone action. Endocrinology 142(4):1587–1594. doi:10.1210/endo.142.4.8095

    CAS  PubMed  Google Scholar 

  28. Le Moellic C, Ouvrard-Pascaud A, Capurro C, Cluzeaud F, Fay M, Jaisser F, Farman N, Blot-Chabaud M (2004) Early nongenomic events in aldosterone action in renal collecting duct cells: PKCalpha activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response. J Am Soc Nephrol 15(5):1145–1160

    CAS  PubMed  Google Scholar 

  29. Haseroth K, Gerdes D, Berger S, Feuring M, Gunther A, Herbst C, Christ M, Wehling M (1999) Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout mice. Biochem Biophys Res Commun 266(1):257–261. doi:10.1006/bbrc.1999.1771

    Article  CAS  PubMed  Google Scholar 

  30. Pitt B, Ferreira JP, Zannad F (2016) Mineralocorticoid receptor antagonists in patients with heart failure: Current experience and future perspectives. Eur Heart J - Cardiovasc Pharmacotherapy

  31. Bienvenu LA, Reichelt ME, Delbridge LM, Young MJ (2013) Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte. Clin Sci (Lond) 125(9):409–421. doi:10.1042/cs20130050

    Article  Google Scholar 

  32. Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242(4878):583–585

    Article  CAS  PubMed  Google Scholar 

  33. Lombès M, Binart N, Oblin ME, Joulin V, Baulieu EE (1993) Characterization of the interaction of the human mineralocorticosteroid receptor with hormone response elements. Biochem J 292(Pt 2):577–583

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP (1992) Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 71(3):503–510

    Article  CAS  PubMed  Google Scholar 

  35. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh FY, Takeda R (1995) Production of aldosterone in isolated rat blood vessels. Hypertension 25(2):170–173

    Article  CAS  PubMed  Google Scholar 

  36. Grossmann C, Gekle M (2009) New aspects of rapid aldosterone signaling. Mol Cell Endocrinol 308(1–2):53–62. doi:10.1016/j.mce.2009.02.005

    Article  CAS  PubMed  Google Scholar 

  37. Booth RE, Johnson JP, Stockand JD (2002) Aldosterone. Adv Physiol Educ 26(1–4):8–20

    Article  PubMed  Google Scholar 

  38. Briet M, Schiffrin EL (2010) Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol 6(5):261–273

    Article  CAS  PubMed  Google Scholar 

  39. Spat A, Hunyady L (2004) Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev 84(2):489–539. doi:10.1152/physrev.00030.2003

    Article  CAS  PubMed  Google Scholar 

  40. Wagner CA (2014) Effect of mineralocorticoids on acid–base balance. Nephron Physiol 128(1–2):26–34. doi:10.1159/000368266

    Article  CAS  PubMed  Google Scholar 

  41. Naray-Fejes-Toth A, Helms MN, Stokes JB, Fejes-Toth G (2004) Regulation of sodium transport in mammalian collecting duct cells by aldosterone-induced kinase, SGK1: structure/function studies. Mol Cell Endocrinol 217(1–2):197–202. doi:10.1016/j.mce.2003.10.043

    Article  CAS  PubMed  Google Scholar 

  42. Stockand JD, Meszaros JG (2003) Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling. Am J Physiol Heart Circ Physiol 284(1):H176–H184. doi:10.1152/ajpheart.00421.2002

    Article  CAS  PubMed  Google Scholar 

  43. Stockand JD (2002) New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282(4):F559–F576. doi:10.1152/ajprenal.00320.2001

    Article  PubMed  Google Scholar 

  44. Farman N, Fay M, Cluzeaud F (2003) Cell-specific expression of three members of the FXYD family along the renal tubule. Ann N Y Acad Sci 986:428–436

    Article  CAS  PubMed  Google Scholar 

  45. Bernardi S, Toffoli B, Zennaro C, Bossi F, Losurdo P, Michelli A, Carretta R, Mulatero P, Fallo F, Veglio F, Fabris B (2015) Aldosterone effects on glomerular structure and function. J Renin-Angiotensin-Aldosterone Syst 16(4):730–738. doi:10.1177/1470320315595568

    Article  CAS  PubMed  Google Scholar 

  46. Nappi JM, Sieg A (2011) Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure. Vasc Health Risk Manag 7:353–363. doi:10.2147/VHRM.S13779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rossier MF, Python M, Maturana AD (2010) Contribution of mineralocorticoid and glucocorticoid receptors to the chronotropic and hypertrophic actions of aldosterone in neonatal rat ventricular myocytes. Endocrinology 151(6):2777–2787. doi:10.1210/en.2009-1375

    Article  CAS  PubMed  Google Scholar 

  48. Nagata K, Somura F, Obata K, Odashima M, Izawa H, Ichihara S, Nagasaka T, Iwase M, Yamada Y, Nakashima N, Yokota M (2002) AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats. Hypertension 40(2):168–174

    Article  CAS  PubMed  Google Scholar 

  49. Lavall D, Selzer C, Schuster P, Lenski M, Adam O, Schaefers H-J, Boehm M, Laufs U (2014) The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation. J Biol Chem. doi:10.1074/jbc.M113.519256

    PubMed  PubMed Central  Google Scholar 

  50. Maiolino G, Azzolini M, Rossi GP (2015) Mineralocorticoid receptor antagonists therapy in resistant hypertension: time to implement guidelines! Frontiers in Cardiovascular Medicine 2:3. doi:10.3389/fcvm.2015.00003

    Article  PubMed  PubMed Central  Google Scholar 

  51. Brilla CG, Zhou G, Matsubara L, Weber KT (1994) Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol 26(7):809–820. doi:10.1006/jmcc.1994.1098

    Article  CAS  PubMed  Google Scholar 

  52. Fullerton MJ, Funder JW (1994) Aldosterone and cardiac fibrosis: in vitro studies. Cardiovasc Res 28(12):1863–1867

    Article  CAS  PubMed  Google Scholar 

  53. Kohler E, Bertschin S, Woodtli T, Resink T, Erne P (1996) Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? J Vasc Res 33(4):315–326

    Article  CAS  PubMed  Google Scholar 

  54. Brilla CG, Matsubara LS, Weber KT (1993) Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension. Am J Cardiol 71(3):12A–16A

    Article  CAS  PubMed  Google Scholar 

  55. Funder JW (2002) New biology of aldosterone, and experimental studies on the selective aldosterone blocker eplerenone. Am Heart J 144(5 Suppl):S8–11

    Article  CAS  PubMed  Google Scholar 

  56. Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK (2000) Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology 141(10):3871–3878. doi:10.1210/endo.141.10.7711

    CAS  PubMed  Google Scholar 

  57. Lijnen P, Petrov V (2000) Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 32(6):865–879. doi:10.1006/jmcc.2000.1129

    Article  CAS  PubMed  Google Scholar 

  58. Brown NJ (2013) Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 9(8):459–469. doi:10.1038/nrneph.2013.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chai W, Garrelds IM, Arulmani U, Schoemaker RG, Lamers JM, Danser AH (2005) Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective? Br J Pharmacol 145(5):664–671. doi:10.1038/sj.bjp.0706220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones--a focus on rapid, nongenomic effects. Pharmacol Rev 52(4):513–556

    CAS  PubMed  Google Scholar 

  61. Funder JW (2005) The nongenomic actions of aldosterone. Endocr Rev 26(3):313–321. doi:10.1210/er.2005-0004

    Article  CAS  PubMed  Google Scholar 

  62. Ashton AW, Le TY, Gomez-Sanchez CE, Morel-Kopp MC, McWhinney B, Hudson A, Mihailidou AS (2015) Role of non-genomic signalling pathways activated by aldosterone during cardiac reperfusion injury. Mol Endocrinol:ME20141410. doi:10.1210/ME.2014–1410

  63. Hayashi H, Kobara M, Abe M, Tanaka N, Gouda E, Toba H, Yamada H, Tatsumi T, Nakata T, Matsubara H (2008) Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res 31(2):363–375. doi:10.1291/hypres.31.363

    Article  CAS  PubMed  Google Scholar 

  64. Chapman K, Holmes M, Seckl J (2013) 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 93(3):1139–1206. doi:10.1152/physrev.00020.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Qin W, Rudolph AE, Bond BR, Rocha R, Blomme EA, Goellner JJ, Funder JW, McMahon EG (2003) Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 93(1):69–76. doi:10.1161/01.RES.0000080521.15238.E5

    Article  CAS  PubMed  Google Scholar 

  66. Myles K, Funder JW (1994) Type I (mineralocorticoid) receptors in the guinea pig. Am J Phys 267(2 Pt 1):E268–E272

    CAS  Google Scholar 

  67. Mihailidou AS, Loan Le TY, Mardini M, Funder JW (2009) Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 54(6):1306–1312. doi:10.1161/HYPERTENSIONAHA.109.136242

    Article  CAS  PubMed  Google Scholar 

  68. Ohtake M, Hattori T, Murase T, Takahashi K, Takatsu M, Ohtake M, Miyachi M, Watanabe S, Cheng XW, Murohara T, Nagata K (2014) Glucocorticoids activate cardiac mineralocorticoid receptors in adrenalectomized Dahl salt-sensitive rats. Nagoya J Med Sci 76(1–2):59–72

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Fujita T (2008) Aldosterone in salt-sensitive hypertension and metabolic syndrome. J Mol Med (Berl) 86(6):729–734. doi:10.1007/s00109-008-0343-1

    Article  CAS  Google Scholar 

  70. Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, Fujita T (2012) Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension 59(2):500–506. doi:10.1161/HYPERTENSIONAHA.111.185520

    Article  CAS  PubMed  Google Scholar 

  71. Kitada K, Nakano D, Liu Y, Fujisawa Y, Hitomi H, Shibayama Y, Shibata H, Nagai Y, Mori H, Masaki T, Kobori H, Nishiyama A (2012) Oxidative stress-induced glomerular mineralocorticoid receptor activation limits the benefit of salt reduction in Dahl salt-sensitive rats. PLoS One 7(7):e41896. doi:10.1371/journal.pone.0041896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hirata A, Maeda N, Nakatsuji H, Hiuge-Shimizu A, Okada T, Funahashi T, Shimomura I (2012) Contribution of glucocorticoid-mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction. Biochem Biophys Res Commun 419(2):182–187. doi:10.1016/j.bbrc.2012.01.139

    Article  CAS  PubMed  Google Scholar 

  73. Zhu D, Rashdan NA, Chapman KE, Hadoke PW, MacRae VE (2016) A novel role for the mineralocorticoid receptor in glucocorticoid driven vascular calcification. Vasc Pharmacol. doi:10.1016/j.vph.2016.04.005

    Google Scholar 

  74. Rafiq K, Nakano D, Ihara G, Hitomi H, Fujisawa Y, Ohashi N, Kobori H, Nagai Y, Kiyomoto H, Kohno M, Nishiyama A (2011) Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats. J Hypertens 29(2):290–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Agarwal AK, Mune T, Monder C, White PC (1994) NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase. Cloning and characterization of cDNA from sheep kidney. J Biol Chem 269(42):25959–25962

    CAS  PubMed  Google Scholar 

  76. Roland BL, Funder JW (1996) Localization of 11beta-hydroxysteroid dehydrogenase type 2 in rat tissues: in situ studies. Endocrinology 137(3):1123–1128. doi:10.1210/endo.137.3.8603583

    CAS  PubMed  Google Scholar 

  77. Hirasawa G, Sasano H, Takahashi K, Fukushima K, Suzuki T, Hiwatashi N, Toyota T, Krozowski ZS, Nagura H (1997) Colocalization of 11 beta-hydroxysteroid dehydrogenase type II and mineralocorticoid receptor in human epithelia. J Clin Endocrinol Metab 82(11):3859–3863. doi:10.1210/jcem.82.11.4337

    CAS  PubMed  Google Scholar 

  78. Suzuki T, Sasano H, Suzuki S, Hirasawa G, Takeyama J, Muramatsu Y, Date F, Nagura H, Krozowski ZS (1998) 11Beta-hydroxysteroid dehydrogenase type 2 in human lung: possible regulator of mineralocorticoid action. J Clin Endocrinol Metab 83(11):4022–4025. doi:10.1210/jcem.83.11.5227

    CAS  PubMed  Google Scholar 

  79. Olivera WG, Ciccolella DE, Barquin N, Ridge KM, Rutschman DH, Yeates DB, Sznajder JI (2000) Aldosterone regulates Na,K-ATPase and increases lung edema clearance in rats. Am J Respir Crit Care Med 161 (2 Pt 1):567–573. doi:10.1164/ajrccm.161.2.9808050

  80. Carlone S, Palange P, Mannix ET, Salatto MP, Serra P, Weinberger MH, Aronoff GR, Cockerill EM, Manfredi F, Farber MO (1989) Atrial natriuretic peptide, renin and aldosterone in obstructive lung disease and heart failure. Am J Med Sci 298(4):243–248

    Article  CAS  PubMed  Google Scholar 

  81. Takada M, Yai H, Komazaki S (1997) In vivo treatment of bullfrog tadpoles with aldosterone potentiates ACh-receptor channels, but not amiloride-blockable Na+ channels in the skin. Zool Sci 14(6):883–886. doi:10.2108/zsj.14.883

    Article  CAS  PubMed  Google Scholar 

  82. Holbird D, Jensik P, Cox T (2001) Aldosterone upregulates purinergic responses in larval amphibian skin epithelium. J Comp Physiol B 171(5):413–420

    Article  CAS  PubMed  Google Scholar 

  83. Urbach V, Van Kerkhove E, Maguire D, Harvey BJ (1996) Rapid activation of KATP channels by aldosterone in principal cells of frog skin. J Physiol 491(Pt 1):111–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Voute CL, Thummel J, Brenner M (1975) Aldosterone effect in the epithelium of the frog skin-a new story about an old enzyme. J Steroid Biochem 6(7):1175–1179

    Article  CAS  PubMed  Google Scholar 

  85. Mitts TF, Bunda S, Wang Y, Hinek A (2010) Aldosterone and mineralocorticoid receptor antagonists modulate elastin and collagen deposition in human skin. J Invest Dermatol 130(10):2396–2406. doi:10.1038/jid.2010.155

    Article  CAS  PubMed  Google Scholar 

  86. Terao M, Itoi S, Murota H, Katayama I (2013) Expression profiles of cortisol-inactivating enzyme, 11beta-hydroxysteroid dehydrogenase-2, in human epidermal tumors and its role in keratinocyte proliferation. Exp Dermatol 22(2):98–101. doi:10.1111/exd.12075

    Article  CAS  PubMed  Google Scholar 

  87. Chai W, Hofland J, Jansen PM, Garrelds IM, de Vries R, van den Bogaerdt AJ, Feelders RA, de Jong FH, Danser AH (2010) Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors? J Hypertens 28(5):1044–1053. doi:10.1097/HJH.0b013e328335c381

    Article  CAS  PubMed  Google Scholar 

  88. van Uum SH, Hermus AR, Smits P, Thien T, Lenders JW (1998) The role of 11 beta-hydroxysteroid dehydrogenase in the pathogenesis of hypertension. Cardiovasc Res 38(1):16–24

    Article  PubMed  Google Scholar 

  89. Ferrari P (2010) The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim Biophys Acta (BBA) - Mol Basis Dis 1802(12):1178–1187. doi:10.1016/j.bbadis.2009.10.017

    Article  CAS  Google Scholar 

  90. van der Velden VH, Naber BA, van der Spoel P, Hoogsteden HC, Versnel MA (1998) Cytokines and glucocorticoids modulate human bronchial epithelial cell peptidases. Cytokine 10(1):55–65. doi:10.1006/cyto.1997.0257

    Article  PubMed  Google Scholar 

  91. Hunter RW, Ivy JR, Bailey MA (2014) Glucocorticoids and renal Na + transport: implications for hypertension and salt sensitivity. J Physiol 592(8):1731–1744. doi:10.1113/jphysiol.2013.267609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Latouche C, Sainte-Marie Y, Steenman M, Castro Chaves P, Naray-Fejes-Toth A, Fejes-Toth G, Farman N, Jaisser F (2010) Molecular signature of mineralocorticoid receptor signaling in cardiomyocytes: from cultured cells to mouse heart. Endocrinology 151(9):4467–4476. doi:10.1210/en.2010-0237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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(12):5264–5268. doi:10.1210/endo.137.12.8940344

    CAS  PubMed  Google Scholar 

  94. Hadoke PWF, Iqbal J, Walker BR (2009) Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br J Pharmacol 156(5):689–712. doi:10.1111/j.1476-5381.2008.00047.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sheppard KE, Autelitano DJ (2002) 11Beta-hydroxysteroid dehydrogenase 1 transforms 11-dehydrocorticosterone into transcriptionally active glucocorticoid in neonatal rat heart. Endocrinology 143(1):198–204. doi:10.1210/endo.143.1.8583

    CAS  PubMed  Google Scholar 

  96. Chai W, Danser AHJ (2006) Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn Schmiedeberg’s Arch Pharmacol 374(3):153–162. doi:10.1007/s00210-006-0107-9

    Article  CAS  Google Scholar 

  97. Reil J-C, Hohl M, Selejan S, Lipp P, Drautz F, Kazakow A, Münz BM, Müller P, Steendijk P, Reil G-H, Allessie MA, Böhm M, Neuberger H-R (2012) Aldosterone promotes atrial fibrillation. Eur Heart J 33(16):2098–2108

    Article  CAS  PubMed  Google Scholar 

  98. Briet M, Schiffrin EL (2013) Vascular actions of aldosterone. J Vasc Res 50(2):89–99. doi:10.1159/000345243

    Article  CAS  PubMed  Google Scholar 

  99. Struthers A, Krum H, Williams GH (2008) A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol 31(4):153–158. doi:10.1002/clc.20324

    Article  PubMed  Google Scholar 

  100. Weinberger MH, Roniker B, Krause SL, Weiss RJ (2002) Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 15(8):709–716

    Article  CAS  PubMed  Google Scholar 

  101. Funder JW (2013) Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine. Integr Blood Press Control 6:129–138. doi:10.2147/IBPC.S13783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, Nowack C, Kolkhof P, Kim SY, Zannad F (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(31):2453–2463. doi:10.1093/eurheartj/eht187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Filippatos G, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim S-Y, Nowack C, Palombo G, Kolkhof P, Kimmeskamp-Kirschbaum N, Pieper A, Pitt B (2016) A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. EurHeart J

  104. Sato N, Ajioka M, Yamada T, Kato M, Myoishi M, Yamada T, Kim SY, Nowack C, Kolkhof P, Shiga T (2016) A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circ J 80(5):1113–1122. doi:10.1253/circj.CJ-16-0122

    Article  PubMed  Google Scholar 

  105. Fraccarollo D, Galuppo P, Schraut S, Kneitz S, van Rooijen N, Ertl G, Bauersachs J (2008) Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension 51(4):905–914. doi:10.1161/HYPERTENSIONAHA.107.100941

    Article  CAS  PubMed  Google Scholar 

  106. Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Ohno K, Fujii M, Taniguchi A, Hamatani T, Nozato Y, Kataoka K, Morigami N, Ohnishi M, Kinoshita M, Horie M (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107(20):2559–2565. doi:10.1161/01.cir.0000068340.96506.0f

    Article  CAS  PubMed  Google Scholar 

  107. Montalescot G, Pitt B, Lopez de Sa E, Hamm CW, Flather M, Verheugt F, Shi H, Turgonyi E, Orri M, Vincent J, Zannad F (2014) Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind reminder study. Eur Heart J 35(34):2295–2302. doi:10.1093/eurheartj/ehu164

    Article  CAS  PubMed  Google Scholar 

  108. Adamopoulos C, Ahmed A, Fay R, Angioi M, Filippatos G, Vincent J, Pitt B, Zannad F (2009) Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial. Eur J Heart Fail 11(11):1099–1105. doi:10.1093/eurjhf/hfp136

    Article  CAS  PubMed  Google Scholar 

  109. Fraccarollo D, Galuppo P, Sieweke J-T, Napp LC, Grobbecker P, Bauersachs J (2015) Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone. ESC Heart Failure 2(3):150–158. doi:10.1002/ehf2.12053

    Article  Google Scholar 

  110. 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(6):C532–C540. doi:10.1152/ajpcell.00203.2012

    Article  CAS  PubMed  Google Scholar 

  111. Gros R, Ding Q, Sklar LA, Prossnitz EE, Arterburn JB, Chorazyczewski J, Feldman RD (2011) GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension 57(3):442–451. doi:10.1161/HYPERTENSIONAHA.110.161653

    Article  CAS  PubMed  Google Scholar 

  112. Hermidorff MM, Faria Gde O, Amancio Gde C, de Assis LV, Isoldi MC (2015) Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways? Biochem Cell Biol 93(1):83–93. doi:10.1139/bcb-2014-0110

    Article  CAS  PubMed  Google Scholar 

  113. de Kloet ER, Reul JM, van den Bosch FR, Tonnaer JA, Saito H (1987) Ginsenoside RG1 and corticosteroid receptors in rat brain. Endocrinol Jpn 34(2):213–220

    Article  PubMed  Google Scholar 

  114. Dorrance AM, Osborn HL, Grekin R, Webb RC (2001) Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats. Am J Physiol Regul Integr Comp Physiol 281(3):R944–R950

    CAS  PubMed  Google Scholar 

  115. Karssen AM, Meijer OC, van der Sandt IC, Lucassen PJ, de Lange EC, de Boer AG, de Kloet ER (2001) Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142(6):2686–2694. doi:10.1210/endo.142.6.8213

    Article  CAS  PubMed  Google Scholar 

  116. Wyrwoll CS, Holmes MC, Seckl JR (2011) 11β-Hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol 32(3):265–286. doi:10.1016/j.yfrne.2010.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Geerling JC, Kawata M, Loewy AD (2006) Aldosterone-sensitive neurons in the rat central nervous system. J Comp Neurol 494(3):515–527. doi:10.1002/cne.20808

    Article  PubMed  Google Scholar 

  118. Formenti S, Schoorlemmer GHM, Moreira TS, E. C (2008) Central nervous system and aldosterone: role on cardiovascular control and hydro-electrolytic homeostasis. Braz Arch Health Sci 33:54–63

  119. Evans LC, Ivy JR, Wyrwoll C, McNairn JA, Menzies RI, Christensen TH, Al-Dujaili EA, Kenyon CJ, Mullins JJ, Seckl JR, Holmes MC, Bailey MA (2016) Conditional deletion of Hsd11b2 in the brain causes salt appetite and hypertension. Circulation 133(14):1360–1370. doi:10.1161/CIRCULATIONAHA.115.019341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fujita M, Fujita T (2016) The role of CNS in the effects of salt on blood pressure. Curr Hypertens Rep 18(2):10. doi:10.1007/s11906-015-0620-7

    Article  PubMed  Google Scholar 

  121. Gomez-Sanchez EP (2014) Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis. Steroids 91:20–31. doi:10.1016/j.steroids.2014.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Toda N, Nakanishi S, Tanabe S (2013) Aldosterone affects blood flow and vascular tone regulated by endothelium-derived NO: therapeutic implications. Br J Pharmacol 168(3):519–533. doi:10.1111/j.1476-5381.2012.02194.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Park JB, Schiffrin EL (2002) Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens 15(2 Pt 1):164–169

    Article  CAS  PubMed  Google Scholar 

  124. Park JB, Schiffrin EL (2001) ETA receptor antagonist prevents blood pressure elevation and vascular remodeling in aldosterone-infused rats. Hypertension 37(6):1444–1449. doi:10.1161/01.hyp.37.6.1444

    Article  CAS  PubMed  Google Scholar 

  125. Taddei S, Virdis A, Mattei P, Salvetti A (1993) Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 21(6 Pt 2):929–933

    Article  CAS  PubMed  Google Scholar 

  126. Ahmad N, Romero DG, Gomez-Sanchez EP, Gomez-Sanchez CE (2004) Do human vascular endothelial cells produce aldosterone? Endocrinology 145(8):3626–3629. doi:10.1210/en.2004-0081

    Article  CAS  PubMed  Google Scholar 

  127. Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto H (1994) Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem 269(39):24316–24320

    CAS  PubMed  Google Scholar 

  128. 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(6):643–650. doi:10.1161/01.RES.0000159937.05502.d1

    Article  CAS  PubMed  Google Scholar 

  129. Benetos A, Lacolley P, Safar ME (1997) Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 17(6):1152–1156

    Article  CAS  PubMed  Google Scholar 

  130. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL (2002) Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 40(4):504–510

    Article  CAS  PubMed  Google Scholar 

  131. Nakano S, Kobayashi N, Yoshida K, Ohno T, Matsuoka H (2005) Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats. Hypertens Res 28(11):925–936. doi:10.1291/hypres.28.925

    Article  CAS  PubMed  Google Scholar 

  132. Johar S, Cave AC, Narayanapanicker A, Grieve DJ, Shah AM (2006) Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J 20(9):1546–1548. doi:10.1096/fj.05-4642fje

    Article  CAS  PubMed  Google Scholar 

  133. Iwashima F, Yoshimoto T, Minami I, Sakurada M, Hirono Y, Hirata Y (2008) Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology 149(3):1009–1014. doi:10.1210/en.2007-0864

    Article  CAS  PubMed  Google Scholar 

  134. Leopold JA, Dam A, Maron BA, Scribner AW, Liao R, Handy DE, Stanton RC, Pitt B, Loscalzo J (2007) Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med 13(2):189–197 http://www.nature.com/nm/journal/v13/n2/suppinfo/nm1545_S1.html

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT (2002) Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am J Pathol 161(5):1773–1781. doi:10.1016/s0002-9440(10)64454-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Brilla CG, Weber KT (1992) Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 120(6):893–901

    CAS  PubMed  Google Scholar 

  137. Calò LA, Puato M, Schiavo S, Zanardo M, Tirrito C, Pagnin E, Balbi G, Davis PA, Palatini P, Pauletto P (2008) Absence of vascular remodelling in a high angiotensin-II state (Bartter’s and Gitelman’s syndromes): implications for angiotensin II signalling pathways. Nephrol Dial Transplant 23(9):2804–2809. doi:10.1093/ndt/gfn118

    Article  PubMed  CAS  Google Scholar 

  138. Lacolley P, Labat C, Pujol A, Delcayre C, Benetos A, Safar M (2002) Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats: effects of eplerenone. Circulation 106(22):2848–2853

    Article  CAS  PubMed  Google Scholar 

  139. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, McMahon EG, Delyani JA (2002) Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 283(5):H1802–H1810. doi:10.1152/ajpheart.01096.2001

    Article  CAS  PubMed  Google Scholar 

  140. Caprio M, Newfell BG, la Sala A, Baur W, Fabbri A, Rosano G, Mendelsohn ME, Jaffe IZ (2008) Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ Res 102(11):1359–1367. doi:10.1161/circresaha.108.174235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ferreira NS, Cau SB, Silva MA, Manzato CP, Mestriner FL, Matsumoto T, Carneiro FS, Tostes RC (2015) Diabetes impairs the vascular effects of aldosterone mediated by G protein-coupled estrogen receptor activation. Front Pharmacol 6:34. doi:10.3389/fphar.2015.00034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. McGraw AP, McCurley A, Preston IR, Jaffe IZ (2013) Mineralocorticoid receptors in vascular disease: connecting molecular pathways to clinical implications. Curr Atheroscler Rep 15(7):340. doi:10.1007/s11883-013-0340-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Briones AM, Nguyen Dinh Cat A, Callera GE, Yogi A, Burger D, He Y, Correa JW, Gagnon AM, Gomez-Sanchez CE, Gomez-Sanchez EP, Sorisky A, Ooi TC, Ruzicka M, Burns KD, Touyz RM (2012) Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. Hypertension 59(5):1069–1078. doi:10.1161/hypertensionaha.111.190223

    Article  CAS  PubMed  Google Scholar 

  144. 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 100(24):14211–14216. doi:10.1073/pnas.2336140100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Schinner S, Willenberg HS, Krause D, Schott M, Lamounier-Zepter V, Krug AW, Ehrhart-Bornstein M, Bornstein SR, Scherbaum WA (2007) Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway. Int J Obes 31(5):864–870. doi:10.1038/sj.ijo.0803508

    CAS  Google Scholar 

  146. Calhoun DA, Sharma K (2010) The role of aldosteronism in causing obesity-related cardiovascular risk. Cardiol Clin 28(3):517–527. doi:10.1016/j.ccl.2010.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  147. Vecchiola A, Lagos CF, Carvajal CA, Baudrand R, Fardella CE (2016) Aldosterone production and signaling dysregulation in obesity. Curr Hypertens Rep 18(3):20. doi:10.1007/s11906-016-0626-9

    Article  PubMed  CAS  Google Scholar 

  148. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH (2008) The metabolic syndrome. Endocr Rev 29(7):777–822. doi:10.1210/er.2008-0024

    Article  CAS  PubMed  Google Scholar 

  149. Kawarazaki W, Fujita T (2016) The role of aldosterone in obesity-related hypertension. Am J Hypertens 29(4):415–423. doi:10.1093/ajh/hpw003

    Article  PubMed  Google Scholar 

  150. Kargi AY, Iacobellis G (2014) Adipose tissue and adrenal glands: novel pathophysiological mechanisms and clinical applications. Int J Endocrinol 2014:8. doi:10.1155/2014/614074

    Article  CAS  Google Scholar 

  151. Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA (2007) Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care 30(9):2349–2354. doi:10.2337/dc07-0525

    Article  CAS  PubMed  Google Scholar 

  152. Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, Rabbia F, Federspil G, Mulatero P (2006) Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 91(2):454–459. doi:10.1210/jc.2005-1733

    Article  CAS  PubMed  Google Scholar 

  153. Fallo F, Pilon C, Urbanet R (2012) Primary aldosteronism and metabolic syndrome. Horm Metab Res 44(3):208–214. doi:10.1055/s-0031-1295412

    Article  CAS  PubMed  Google Scholar 

  154. Vaidya A, Underwood PC, Hopkins PN, Jeunemaitre X, Ferri C, Williams GH, Adler GK (2013) Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension 61(4):886–893. doi:10.1161/HYPERTENSIONAHA.111.00662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Garg R, Kneen L, Williams GH, Adler GK (2014) Effect of mineralocorticoid receptor antagonist on insulin resistance and endothelial function in obese subjects. Diabetes Obes Metab 16(3):268–272. doi:10.1111/dom.12224

    Article  CAS  PubMed  Google Scholar 

  156. Garg R, Hurwitz S, Williams GH, Hopkins PN, Adler GK (2010) Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab 95(4):1986–1990. doi:10.1210/jc.2009-2521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Williams TA, Monticone S, Urbanet R, Bertello C, Giraudo G, Vettor R, Fallo F, Veglio F, Mulatero P (2012) Genes implicated in insulin resistance are down-regulated in primary aldosteronism patients. Mol Cell Endocrinol 355(1):162–168. doi:10.1016/j.mce.2012.02.007

    Article  CAS  PubMed  Google Scholar 

  158. Harada E, Mizuno Y, Katoh D, Kashiwagi Y, Morita S, Nakayama Y, Yoshimura M, Masuzaki H, Saito Y, Yasue H (2013) Increased urinary aldosterone excretion is associated with subcutaneous not visceral, adipose tissue area in obese individuals: a possible manifestation of dysfunctional subcutaneous adipose tissue. Clin Endocrinol 79(4):510–516. doi:10.1111/cen.12083

    Article  CAS  Google Scholar 

  159. Viengchareun S, Penfornis P, Zennaro MC, Lombes M (2001) Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. Am J Physiol Endocrinol Metab 280(4):E640–E649

    CAS  PubMed  Google Scholar 

  160. Feldman RD, Gros R (2011) Unraveling the mechanisms underlying the rapid vascular effects of steroids: sorting out the receptors and the pathways. Br J Pharmacol 163(6):1163–1169. doi:10.1111/j.1476-5381.2011.01366.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Spach C, Streeten DH (1964) Retardation of sodium exchange in dog erythrocytes by physiological concentrations of aldosterone, in vitro. J Clin Invest 43:217–227. doi:10.1172/JCI104906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Klein K, Henk W (1964) Klinisch-experimentelle Untersuchungen über den Einfluss von Aldosteron auf Hämodynamik und Gerinnung. J Clin Invest 43:217–227

    Article  Google Scholar 

  163. Streeten DH, Hirschowitz BI, Henley KS, Pollard HM (1957) Effects of adrenocortical steroids on the propulsive motility of small intestine. Am J Phys 189(1):108–112

    CAS  Google Scholar 

  164. Wehling M, Losel R (2006) Non-genomic steroid hormone effects: membrane or intracellular receptors? J Steroid Biochem Mol Biol 102(1–5):180–183. doi:10.1016/j.jsbmb.2006.09.016

    Article  CAS  PubMed  Google Scholar 

  165. Hammes SR, Levin ER (2007) Extranuclear steroid receptors: nature and actions. Endocr Rev 28(7):726–741. doi:10.1210/er.2007-0022

    Article  CAS  PubMed  Google Scholar 

  166. Perez MH, Cormack J, Mallinson D, Mutungi G (2013) A membrane glucocorticoid receptor mediates the rapid/non-genomic actions of glucocorticoids in mammalian skeletal muscle fibres. J Physiol 591(Pt 20):5171–5185. doi:10.1113/jphysiol.2013.256586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Strehl C, Gaber T, Lowenberg M, Hommes DW, Verhaar AP, Schellmann S, Hahne M, Fangradt M, Wagegg M, Hoff P, Scheffold A, Spies CM, Burmester GR, Buttgereit F (2011) Origin and functional activity of the membrane-bound glucocorticoid receptor. Arthritis Rheum 63(12):3779–3788. doi:10.1002/art.30637

    Article  CAS  PubMed  Google Scholar 

  168. Wehling M, Kasmayr J, Theisen K (1991) Rapid effects of mineralocorticoids on sodium-proton exchanger: genomic or nongenomic pathway? Am J Phys 260(5 Pt 1):E719–E726

    CAS  Google Scholar 

  169. Wildling L, Hinterdorfer P, Kusche-Vihrog K, Treffner Y, Oberleithner H (2009) Aldosterone receptor sites on plasma membrane of human vascular endothelium detected by a mechanical nanosensor. Pflugers Arch 458(2):223–230. doi:10.1007/s00424-008-0615-1

    Article  CAS  PubMed  Google Scholar 

  170. Grossmann C, Benesic A, Krug AW, Freudinger R, Mildenberger S, Gassner B, Gekle M (2005) Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol Endocrinol 19(7):1697–1710. doi:10.1210/me.2004-0469

    Article  CAS  PubMed  Google Scholar 

  171. Chai W, Garrelds IM, de Vries R, Batenburg WW, van Kats JP, Danser AH (2005) Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II. Hypertension 46(4):701–706. doi:10.1161/01.HYP.0000182661.98259.4f

    Article  CAS  PubMed  Google Scholar 

  172. Zhou ZH, Bubien JK (2001) Nongenomic regulation of ENaC by aldosterone. Am J Physiol Cell Physiol 281(4):C1118–C1130

    CAS  PubMed  Google Scholar 

  173. Fuller PJ, Young MJ (2005) Mechanisms of mineralocorticoid action. Hypertension 46(6):1227–1235. doi:10.1161/01.hyp.0000193502.77417.17

    Article  CAS  PubMed  Google Scholar 

  174. Uhrenholt TR, Schjerning J, Hansen PB, Norregaard R, Jensen BL, Sorensen GL, Skott O (2003) Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone. Circ Res 93(12):1258–1266. doi:10.1161/01.res.0000106135.02935.e1

    Article  CAS  PubMed  Google Scholar 

  175. Michea L, Delpiano AM, Hitschfeld C, Lobos L, Lavandero S, Marusic ET (2005) Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. Endocrinology 146(3):973–980. doi:10.1210/en.2004-1130

    Article  CAS  PubMed  Google Scholar 

  176. Grossmann C, Freudinger R, Mildenberger S, Husse B, Gekle M (2008) EF domains are sufficient for nongenomic mineralocorticoid receptor actions. J Biol Chem 283(11):7109–7116. doi:10.1074/jbc.M708751200

    Article  CAS  PubMed  Google Scholar 

  177. Moura AM, Worcel M (1984) Direct action of aldosterone on transmembrane 22Na efflux from arterial smooth muscle. Rapid and delayed effects. Hypertension 6(3):425–430

    Article  CAS  PubMed  Google Scholar 

  178. Sato A, Liu JP, Funder JW (1997) Aldosterone rapidly represses protein kinase C activity in neonatal rat cardiomyocytes in vitro. Endocrinology 138(8):3410–3416. doi:10.1210/endo.138.8.5352

    Article  CAS  PubMed  Google Scholar 

  179. Barbato JC, Mulrow PJ, Shapiro JI, Franco-Saenz R (2002) Rapid effects of aldosterone and spironolactone in the isolated working rat heart. Hypertension 40(2):130–135

    Article  CAS  PubMed  Google Scholar 

  180. Mihailidou AS, Mardini M, Funder JW (2004) Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology 145(2):773–780. doi:10.1210/en.2003-1137

    Article  CAS  PubMed  Google Scholar 

  181. Mihailidou AS, Buhagiar KA, Rasmussen HH (1998) Na+ influx and Na(+)-K+ pump activation during short-term exposure of cardiac myocytes to aldosterone. Am J Phys 274(1 Pt 1):C175–C181

    CAS  Google Scholar 

  182. Matsui S, Satoh H, Kawashima H, Nagasaka S, Niu CF, Urushida T, Katoh H, Watanabe Y, Hayashi H (2007) Non-genomic effects of aldosterone on intracellular ion regulation and cell volume in rat ventricular myocytes. Can J Physiol Pharmacol 85(2):264–273. doi:10.1139/y07-017

    Article  CAS  PubMed  Google Scholar 

  183. De Giusti VC, Nolly MB, Yeves AM, Caldiz CI, Villa-Abrille MC, Chiappe de Cingolani GE, Ennis IL, Cingolani HE, Aiello EA (2011) Aldosterone stimulates the cardiac Na(+)/H(+) exchanger via transactivation of the epidermal growth factor receptor. Hypertension 58(5):912–919. doi:10.1161/HYPERTENSIONAHA.111.176024

    Article  CAS  PubMed  Google Scholar 

  184. Ren Y, D’Ambrosio MA, Garvin JL, Leung P, Kutskill K, Wang H, Peterson EL, Carretero OA (2014) Aldosterone sensitizes connecting tubule glomerular feedback via the aldosterone receptor GPR30. Am J Physiol Renal Physiol 307(4):F427–F434. doi:10.1152/ajprenal.00072.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Feldman RD, Limbird LE (2016) GPER (GPR30): a nongenomic receptor (GPCR) for steroid hormones with implications for cardiovascular disease and cancer. Annu Rev Pharmacol Toxicol. doi:10.1146/annurev-pharmtox-010716-104651

    PubMed  Google Scholar 

  186. Cingolani HE, Ennis IL (2007) Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 115(9):1090–1100. doi:10.1161/CIRCULATIONAHA.106.626929

    Article  PubMed  Google Scholar 

  187. Martinez FA (2010) Aldosterone inhibition and cardiovascular protection: more important than it once appeared. Cardiovasc Drugs Ther 24(4):345–350. doi:10.1007/s10557-010-6256-6

    Article  CAS  PubMed  Google Scholar 

  188. Weil BR, Manukyan MC, Herrmann JL, Wang Y, Abarbanell AM, Poynter JA, Meldrum DR (2010) Signaling via GPR30 protects the myocardium from ischemia/reperfusion injury. Surgery 148(2):436–443. doi:10.1016/j.surg.2010.03.011

    Article  PubMed  Google Scholar 

  189. Filice E, Recchia AG, Pellegrino D, Angelone T, Maggiolini M, Cerra MC (2009) A new membrane G protein-coupled receptor (GPR30) is involved in the cardiac effects of 17beta-estradiol in the male rat. J Physiol Pharmacol 60(4):3–10

    CAS  PubMed  Google Scholar 

  190. Kang S, Liu Y, Sun D, Zhou C, Liu A, Xu C, Hao Y, Li D, Yan C, Sun H (2012) Chronic activation of the G protein-coupled receptor 30 with agonist G-1 attenuates heart failure. PLoS One 7(10):e48185. doi:10.1371/journal.pone.0048185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Deschamps AM, Murphy E (2009) Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am J Physiol Heart Circ Physiol 297(5):H1806–H1813. doi:10.1152/ajpheart.00283.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. De Francesco EM, Angelone T, Pasqua T, Pupo M, Cerra MC, Maggiolini M (2013) GPER mediates cardiotropic effects in spontaneously hypertensive rat hearts. PLoS One 8(8):e69322. doi:10.1371/journal.pone.0069322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Brailoiu GC, Benamar K, Arterburn JB, Gao E, Rabinowitz JE, Koch WJ, Brailoiu E (2013) Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation. J Physiol 591(Pt 17):4223–4235. doi:10.1113/jphysiol.2013.257204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. De Giusti VC, Orlowski A, Ciancio MC, Espejo MS, Gonano LA, Caldiz CI, Vila Petroff MG, Villa-Abrille MC, Aiello EA (2015) Aldosterone stimulates the cardiac sodium/bicarbonate cotransporter via activation of the g protein-coupled receptor gpr30. J Mol Cell Cardiol 89(Pt B):260–267. doi:10.1016/j.yjmcc.2015.10.024

    Article  CAS  PubMed  Google Scholar 

  195. Orlowski A, De Giusti VC, Ciancio MC, Espejo MS, Aiello EA (2016) The cardiac electrogenic sodium/bicarbonate cotransporter (NBCe1) is activated by aldosterone through the G protein-coupled receptor 30 (GPR 30). Channels (Austin):0. doi:10.1080/19336950.2016.1195533

  196. Good DW (2007) Nongenomic actions of aldosterone on the renal tubule. Hypertension 49(4):728–739. doi:10.1161/01.HYP.0000259797.48382.b2

    Article  CAS  PubMed  Google Scholar 

  197. Boldyreff B, Wehling M (2003) Non-genomic actions of aldosterone: mechanisms and consequences in kidney cells. Nephrology Dial Transplant 18(9):1693–1695. doi:10.1093/ndt/gfg265

    Article  CAS  Google Scholar 

  198. Thomas W, Harvey BJ (2011) Mechanisms underlying rapid aldosterone effects in the kidney. Annu Rev Physiol 73:335–357. doi:10.1146/annurev-physiol-012110-142222

    Article  CAS  PubMed  Google Scholar 

  199. Harvey BJ, Alzamora R, Stubbs AK, Irnaten M, McEneaney V, Thomas W (2008) Rapid responses to aldosterone in the kidney and colon. J Steroid Biochem Mol Biol 108(3–5):310–317. doi:10.1016/j.jsbmb.2007.09.005

    Article  CAS  PubMed  Google Scholar 

  200. Fuster DG, Alexander RT (2014) Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflugers Arch 466(1):61–76. doi:10.1007/s00424-013-1408-8

    Article  CAS  PubMed  Google Scholar 

  201. Oberleithner H, Weigt M, Westphale HJ, Wang W (1987) Aldosterone activates Na+/H+ exchange and raises cytoplasmic pH in target cells of the amphibian kidney. Proc Natl Acad Sci U S A 84(5):1464–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Vilella S, Guerra L, Helmle-Kolb C, Murer H (1992) Aldosterone actions on basolateral Na+/H+ exchange in Madin-Darby canine kidney cells. Pflugers Arch 422(1):9–15

    Article  CAS  PubMed  Google Scholar 

  203. Gekle M, Golenhofen N, Oberleithner H, Silbernagl S (1996) Rapid activation of Na+/H+ exchange by aldosterone in renal epithelial cells requires Ca2+ and stimulation of a plasma membrane proton conductance. Proc Natl Acad Sci U S A 93(19):10500–10504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gekle M, Silbernagl S, Wünsch S (1998) Non-genomic action of the mineralocorticoid aldosterone on cytosolic sodium in cultured kidney cells. J Physiol 511(Pt 1):255–263. doi:10.1111/j.1469-7793.1998.255bi.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Gekle M, Freudinger R, Mildenberger S, Schenk K, Marschitz I, Schramek H (2001) Rapid activation of Na+/H+−exchange in MDCK cells by aldosterone involves MAP-kinases ERK 1/2. Pflugers Arch 441(6):781–786. doi:10.1007/s004240000507

    Article  CAS  PubMed  Google Scholar 

  206. Gekle M, Freudinger R, Mildenberger S, Silbernagl S (2002) Aldosterone interaction with epidermal growth factor receptor signaling in MDCK cells. Am J Physiol Renal Physiol 282(4):F669–F679. doi:10.1152/ajprenal.00159.2001

    Article  CAS  PubMed  Google Scholar 

  207. Drumm K, Kress TR, Gassner B, Krug AW, Gekle M (2006) Aldosterone stimulates activity and surface expression of NHE3 in human primary proximal tubule epithelial cells (RPTEC). Cell Physiol Biochem 17(1–2):21–28. doi:10.1159/000091456

    Article  CAS  PubMed  Google Scholar 

  208. Pinto V, Pinho MJ, Hopfer U, Jose PA, Soares-da-Silva P (2008) Oxidative stress and the genomic regulation of aldosterone-stimulated NHE1 activity in SHR renal proximal tubular cells. Mol Cell Biochem 310(1–2):191–201. doi:10.1007/s11010-007-9680-6

    Article  CAS  PubMed  Google Scholar 

  209. Markos F, Healy V, Harvey BJ (2005) Aldosterone rapidly activates Na+/H+ exchange in M-1 cortical collecting duct cells via a PKC-MAPK pathway. Nephron Physiology 99(1):p1–p9

    Article  CAS  PubMed  Google Scholar 

  210. Harvey BJ, Higgins M (2000) Nongenomic effects of aldosterone on Ca2+ in M-1 cortical collecting duct cells. Kidney Int 57(4):1395–1403. doi:10.1046/j.1523-1755.2000.00981.x

    Article  CAS  PubMed  Google Scholar 

  211. Good DW, George T, Watts BA 3rd (2002) Aldosterone inhibits HCO absorption via a nongenomic pathway in medullary thick ascending limb. Am J Physiol Renal Physiol 283(4):F699–F706. doi:10.1152/ajprenal.00133.2002

    Article  PubMed  Google Scholar 

  212. Good DW, George T, Watts BA 3rd (2006) Nongenomic regulation by aldosterone of the epithelial NHE3 Na(+)/H(+) exchanger. Am J Physiol Cell Physiol 290(3):C757–C763. doi:10.1152/ajpcell.00391.2005

    Article  CAS  PubMed  Google Scholar 

  213. Watts BA 3rd, George T, Good DW (2006) Aldosterone inhibits apical NHE3 and HCO3− absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb. Am J Physiol Renal Physiol 291(5):F1005–F1013. doi:10.1152/ajprenal.00507.2005

    Article  CAS  PubMed  Google Scholar 

  214. Fujii Y, Takemoto F, Katz AI (1990) Early effects of aldosterone on Na-K pump in rat cortical collecting tubules, vol 259. vol 1

  215. Beron J, Mastroberardino L, Spillmann A, Verrey F (1995) Aldosterone modulates sodium kinetics of Na,K-ATPase containing an alpha 1 subunit in A6 kidney cell epithelia. Mol Biol Cell 6(3):261–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Summa V, Mordasini D, Roger F, Bens M, Martin P-Y, Vandewalle A, Verrey F, Féraille E (2001) Short term effect of aldosterone on Na,K-ATPase cell surface expression in kidney collecting duct cells. J Biol Chem 276(50):47087–47093. doi:10.1074/jbc.M107165200

    Article  CAS  PubMed  Google Scholar 

  217. Shahedi M, Laborde K, Bussieres L, Sachs C (1993) Acute and early effects of aldosterone on Na-K-ATPase activity in Madin-Darby canine kidney epithelial cells. Am J Phys 264(6 Pt 2):F1021–F1026

    CAS  Google Scholar 

  218. Pearce D (2001) The role of SGK1 in hormone-regulated sodium transport. Trends Endocrinol Metab 12(8):341–347

    Article  CAS  PubMed  Google Scholar 

  219. Verrey F, Loffing J, Zecevic M, Heitzmann D, Staub O (2003) SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 13(1):21–28

    Article  CAS  PubMed  Google Scholar 

  220. Alvarez de la Rosa D, Gimenez I, Forbush B, Canessa CM (2006) SGK1 activates Na+−K+-ATPase in amphibian renal epithelial cells. Am J Physiol Cell Physiol 290(2):C492–C498. doi:10.1152/ajpcell.00556.2004

    Article  CAS  PubMed  Google Scholar 

  221. Middleton JP, Khan WA, Collinsworth G, Hannun YA, Medford RM (1993) Heterogeneity of protein kinase C-mediated rapid regulation of Na/K-ATPase in kidney epithelial cells. J Biol Chem 268(21):15958–15964

    CAS  PubMed  Google Scholar 

  222. Cheng XJ, Fisone G, Aizman O, Aizman R, Levenson R, Greengard P, Aperia A (1997) PKA-mediated phosphorylation and inhibition of Na(+)-K(+)-ATPase in response to beta-adrenergic hormone. Am J Phys 273(3 Pt 1):C893–C901

    CAS  Google Scholar 

  223. Belusa R, Wang ZM, Matsubara T, Sahlgren B, Dulubova I, Nairn AC, Ruoslahti E, Greengard P, Aperia A (1997) Mutation of the protein kinase C phosphorylation site on rat alpha1 Na+,K+-ATPase alters regulation of intracellular Na+ and pH and influences cell shape and adhesiveness. J Biol Chem 272(32):20179–20184

    Article  CAS  PubMed  Google Scholar 

  224. Salyer SA, Parks J, Barati MT, Lederer ED, Clark BJ, Klein JD, Khundmiri SJ (2013) Aldosterone regulates Na(+), K(+) ATPase activity in human renal proximal tubule cells through mineralocorticoid receptor. Biochim Biophys Acta 1833(10):2143–2152. doi:10.1016/j.bbamcr.2013.05.009

    Article  CAS  PubMed  Google Scholar 

  225. Garty H, Palmer LG (1997) Epithelial sodium channels: function, structure, and regulation. Physiol Rev 77(2):359–396

    CAS  PubMed  Google Scholar 

  226. Bhalla V, Hallows KR (2008) Mechanisms of ENaC regulation and clinical implications. J Am Soc Nephrol 19(10):1845–1854. doi:10.1681/asn.2008020225

    Article  CAS  PubMed  Google Scholar 

  227. Jasti J, Furukawa H, Gonzales EB, Gouaux E (2007) Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449(7160):316–323. doi:10.1038/nature06163

    Article  CAS  PubMed  Google Scholar 

  228. Masilamani S, Kim G-H, Mitchell C, Wade JB, Knepper MA (1999) Aldosterone-mediated regulation of ENaC α, β, and γ subunit proteins in rat kidney. J Clin Investig 104(7):R19–R23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC (1997) Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells. J Am Soc Nephrol 8(12):1813–1822

    CAS  PubMed  Google Scholar 

  230. Epple HJ, Amasheh S, Mankertz J, Goltz M, Schulzke JD, Fromm M (2000) Early aldosterone effect in distal colon by transcriptional regulation of ENaC subunits. Am J Physiol Gastrointest Liver Physiol 278(5):G718–G724

    CAS  PubMed  Google Scholar 

  231. Snyder PM, Olson DR, Kabra R, Zhou R, Steines JC (2004) cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na+ channel through convergent phosphorylation of Nedd4-2. J Biol Chem 279(44):45753–45758. doi:10.1074/jbc.M407858200

    Article  CAS  PubMed  Google Scholar 

  232. Mironova E, Bugaj V, Roos KP, Kohan DE, Stockand JD (2012) Aldosterone-independent regulation of the epithelial Na+ channel (ENaC) by vasopressin in adrenalectomized mice. Proc Natl Acad Sci U S A 109(25):10095–10100. doi:10.1073/pnas.1201978109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Náray-Fejes-Tóth A, Helms MN, Stokes JB, Fejes-Tóth G (2004) Regulation of sodium transport in mammalian collecting duct cells by aldosterone-induced kinase, SGK1: structure/function studies. Mol Cell Endocrinol 217(1–2):197–202. doi:10.1016/j.mce.2003.10.043

    Article  PubMed  CAS  Google Scholar 

  234. Lee IH, Campbell CR, Cook DI, Dinudom A (2008) Regulation of epithelial Na+ channels by aldosterone: role of Sgk1. Clin Exp Pharmacol Physiol 35(2):235–241. doi:10.1111/j.1440-1681.2007.04844.x

    Article  CAS  PubMed  Google Scholar 

  235. Verrey F, Fakitsas P, Adam G, Staub O (2008) Early transcriptional control of ENaC (de)ubiquitylation by aldosterone. Kidney Int 73(6):691–696. doi:10.1038/sj.ki.5002737

    Article  CAS  PubMed  Google Scholar 

  236. Fakitsas P, Adam G, Daidié D, van Bemmelen MX, Fouladkou F, Patrignani A, Wagner U, Warth R, Camargo SMR, Staub O, Verrey F (2007) Early aldosterone-induced gene product regulates the epithelial sodium channel by deubiquitylation. J Am Soc Nephrol 18(4):1084–1092. doi:10.1681/asn.2006080902

    Article  CAS  PubMed  Google Scholar 

  237. Shimkets RA, Lifton R, Canessa CM (1998) In vivo phosphorylation of the epithelial sodium channel. Proc Natl Acad Sci U S A 95(6):3301–3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Zhang Y-H, Alvarez de la Rosa D, Canessa CM, Hayslett JP (2004) Insulin-induced phosphorylation of ENaC correlates with increased sodium channel function in A6 cells. Am J Physiol Cell Physiol 288(1):C141–C147

    PubMed  Google Scholar 

  239. McEneaney V, Dooley R, Yusef YR, Keating N, Quinn U, Harvey BJ, Thomas W (2010) Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line. Mol Cell Endocrinol 325(1–2):8–17. doi:10.1016/j.mce.2010.04.019

    Article  CAS  PubMed  Google Scholar 

  240. Dooley R, Angibaud E, Yusef YR, Thomas W, Harvey BJ (2013) Aldosterone-induced ENaC and basal Na+/K+-ATPase trafficking via protein kinase D1-phosphatidylinositol 4-kinaseIIIβ trans Golgi signalling in M1 cortical collecting duct cells. Mol Cell Endocrinol 372(1–2):86–95. doi:10.1016/j.mce.2013.03.011

    Article  CAS  PubMed  Google Scholar 

  241. Helms MN, Liu L, Liang YY, Al-Khalili O, Vandewalle A, Saxena S, Eaton DC, Ma HP (2005) Phosphatidylinositol 3,4,5-trisphosphate mediates aldosterone stimulation of epithelial sodium channel (ENaC) and interacts with gamma-ENaC. J Biol Chem 280(49):40885–40891. doi:10.1074/jbc.M509646200

    Article  CAS  PubMed  Google Scholar 

  242. Stockand JD, Edinger RS, Eaton DC, Johnson JP (2000) Toward understanding the role of methylation in aldosterone-sensitive Na+ transport. Physiology 15(4):161–165

    CAS  Google Scholar 

  243. Schwartz GJ, Burg MB (1978) Mineralocorticoid effects on cation transport by cortical collecting tubules in vitro. Am J Phys 235(6):F576–F585

    CAS  Google Scholar 

  244. Wingo CS, Kokko JP, Jacobson HR (1985) Effects of in vitro aldosterone on the rabbit cortical collecting tubule. Kidney Int 28(1):51–57

    Article  CAS  PubMed  Google Scholar 

  245. Lindsey SH, Yamaleyeva LM, Brosnihan KB, Gallagher PE, Chappell MC (2011) Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2 rat. Hypertension 58(4):665–671. doi:10.1161/HYPERTENSIONAHA.111.175174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Hofmeister MV, Damkier HH, Christensen BM, Olde B, Fredrik Leeb-Lundberg LM, Fenton RA, Praetorius HA, Praetorius J (2012) 17beta-Estradiol induces nongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1. Am J Physiol Renal Physiol 302(3):F358–F368. doi:10.1152/ajprenal.00343.2011

    Article  CAS  PubMed  Google Scholar 

  247. Christ M, Douwes K, Eisen C, Bechtner G, Theisen K, Wehling M (1995) Rapid effects of aldosterone on sodium transport in vascular smooth muscle cells. Hypertension 25(1):117–123

    Article  CAS  PubMed  Google Scholar 

  248. Christ M, Meyer C, Sippel K, Wehling M (1995) Rapid aldosterone signaling in vascular smooth muscle cells: involvement of phospholipase C, diacylglycerol and protein kinase C alpha. Biochem Biophys Res Commun 213(1):123–129. doi:10.1006/bbrc.1995.2106

    Article  CAS  PubMed  Google Scholar 

  249. Wehling M, Neylon CB, Fullerton M, Bobik A, Funder JW (1995) Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells. Circ Res 76(6):973–979

    Article  CAS  PubMed  Google Scholar 

  250. Christ M, Günther A, Heck M, Schmidt BMW, Falkenstein E, Wehling M (1999) Aldosterone, not estradiol, is the physiological agonist for rapid increases in cAMP in vascular smooth muscle cells. Circulation 99(11):1485–1491. doi:10.1161/01.cir.99.11.1485

    Article  CAS  PubMed  Google Scholar 

  251. Ishizawa K, Izawa Y, Ito H, Miki C, Miyata K, Fujita Y, Kanematsu Y, Tsuchiya K, Tamaki T, Nishiyama A, Yoshizumi M (2005) Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension 46(4):1046–1052. doi:10.1161/01.HYP.0000172622.51973.f5

    Article  CAS  PubMed  Google Scholar 

  252. Callera GE, Touyz RM, Tostes RC, Yogi A, He Y, Malkinson S, Schiffrin EL (2005) Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension 45(4):773–779. doi:10.1161/01.HYP.0000154365.30593.d3

    Article  CAS  PubMed  Google Scholar 

  253. Manegold JC, Falkenstein E, Wehling M, Christ M (1999) Rapid aldosterone effects on tyrosine phosphorylation in vascular smooth muscle cells. Cell Mol Biol (Noisy-le-grand) 45(6):805–813

    CAS  Google Scholar 

  254. Wehling M, Spes CH, Win N, Janson CP, Schmidt BM, Theisen K, Christ M (1998) Rapid cardiovascular action of aldosterone in man. J Clin Endocrinol Metab 83(10):3517–3522. doi:10.1210/jcem.83.10.5203

    CAS  PubMed  Google Scholar 

  255. Schmidt BM, Montealegre A, Janson CP, Martin N, Stein-Kemmesies C, Scherhag A, Feuring M, Christ M, Wehling M (1999) Short term cardiovascular effects of aldosterone in healthy male volunteers. J Clin Endocrinol Metab 84(10):3528–3533. doi:10.1210/jcem.84.10.6020

    CAS  PubMed  Google Scholar 

  256. Romagni P, Rossi F, Guerrini L, Quirini C, Santiemma V (2003) Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis 166(2):345–349

    Article  CAS  PubMed  Google Scholar 

  257. Schmidt BMW, Oehmer S, Delles C, Bratke R, Schneider MP, Klingbeil A, Fleischmann EH, Schmieder RE (2003) Rapid nongenomic effects of aldosterone on human forearm vasculature. Hypertension 42(2):156–160. doi:10.1161/01.Hyp.0000083298.23119.16

    Article  CAS  PubMed  Google Scholar 

  258. Gunaruwan P, Schmitt M, Taylor J, Lee L, Struthers A, Frenneaux M (2002) Lack of rapid aldosterone effects on forearm resistance vasculature in health. J Renin-Angiotensin-Aldosterone Syst 3(2):123–125. doi:10.3317/jraas.2002.013

    Article  CAS  PubMed  Google Scholar 

  259. Gunaruwan P, Schmitt M, Sharman J, Lee L, Struthers A, Frenneaux M (2005) Effects of aldosterone on forearm vasculature in treated chronic heart failure. Am J Cardiol 95(3):412–414. doi:10.1016/j.amjcard.2004.09.047

    Article  CAS  PubMed  Google Scholar 

  260. Liu SL, Schmuck S, Chorazcyzewski JZ, Gros R, Feldman RD (2003) Aldosterone regulates vascular reactivity: short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation 108(19):2400–2406. doi:10.1161/01.cir.0000093188.53554.44

    Article  CAS  PubMed  Google Scholar 

  261. 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(1):169–178

    Article  CAS  PubMed  Google Scholar 

  262. 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(1):169–178. doi:10.1093/cvr/cvn064

    Article  CAS  PubMed  Google Scholar 

  263. Akazawa H, Yabumoto C, Yano M, Kudo-Sakamoto Y, Komuro I (2013) ARB and cardioprotection. Cardiovasc Drugs Ther 27(2):155–160. doi:10.1007/s10557-012-6392-2

    Article  CAS  PubMed  Google Scholar 

  264. Harvey BJ, Doolan CM, Condliffe SB, Renard C, Alzamora R, Urbach V (2002) Non-genomic convergent and divergent signalling of rapid responses to aldosterone and estradiol in mammalian colon. Steroids 67(6):483–491

    Article  CAS  PubMed  Google Scholar 

  265. Singh SK, O’Hara B, Talukder JR, Rajendran VM (2012) Aldosterone induces active K(+) secretion by enhancing mucosal expression of Kcnn4c and Kcnma1 channels in rat distal colon. Am J Physiol Cell Physiol 302(9):C1353–C1360. doi:10.1152/ajpcell.00216.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Naftalin RJ, Zammit PS, Pedley KC (1999) Regional differences in rat large intestinal crypt function in relation to dehydrating capacity in vivo. J Physiol 514(Pt 1):201–210. doi:10.1111/j.1469-7793.1999.201af.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Miró L, Pérez-Bosque A, Maijó M, Amat C, Naftalin RJ, Moretó M (2013) Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability. Am J Physiol Cell Physiol 304(9):C918–C926

    Article  PubMed  CAS  Google Scholar 

  268. Thiagarajah JR, Griffiths NM, Pedley KC, Naftalin RJ (2002) Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by transforming growth factor β and angiotensin II. BMC Gastroenterol 2(1):1–11. doi:10.1186/1471-230x-2-4

    Article  Google Scholar 

  269. Thiagarajah JR, Pedley KC, Naftalin RJ (2001) Evidence of amiloride-sensitive fluid absorption in rat descending colonic crypts from fluorescence recovery of FITC-labelled dextran after photobleaching. J Physiol 536(Pt 2):541–553. doi:10.1111/j.1469-7793.2001.0541c.xd

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Cristia E, Afzal-Ahmed I, Perez-Bosque A, Amat C, Naftalin RJ, Moreto M (2005) Pericryptal myofibroblast growth in rat descending colon induced by low-sodium diets is mediated by aldosterone and not by angiotensin II. J Membr Biol 206(1):53–59. doi:10.1007/s00232-005-0773-4

    Article  CAS  PubMed  Google Scholar 

  271. Moreto M, Cristia E, Perez-Bosque A, Afzal-Ahmed I, Amat C, Naftalin RJ (2005) Aldosterone reduces crypt colon permeability during low-sodium adaptation. J Membr Biol 206(1):43–51. doi:10.1007/s00232-005-0772-5

    Article  CAS  PubMed  Google Scholar 

  272. Fuller PJ, Verity K (1990) Mineralocorticoid receptor gene expression in the gastrointestinal tract: distribution and ontogeny. J Steroid Biochem 36(4):263–267

    Article  CAS  PubMed  Google Scholar 

  273. Will PC, Lebowitz JL, Hopfer U (1980) Induction of amiloride-sensitive sodium transport in the rat colon by mineralocorticoids. Am J Physiol Ren Physiol 238(4):F261–F268

    CAS  Google Scholar 

  274. Kunzelmann K, Mall M (2002) Electrolyte transport in the mammalian colon: mechanisms and implications for disease. Physiol Rev 82(1):245–289. doi:10.1152/physrev.00026.2001

    Article  CAS  PubMed  Google Scholar 

  275. Sweiry JH, Binder HJ (1989) Characterization of aldosterone-induced potassium secretion in rat distal colon. J Clin Invest 83(3):844–851. doi:10.1172/jci113967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Todkar A, Picard N, Loffing-Cueni D, Sorensen MV, Mihailova M, Nesterov V, Makhanova N, Korbmacher C, Wagner CA, Loffing J (2015) Mechanisms of renal control of potassium homeostasis in complete aldosterone deficiency. J Am Soc Nephrol 26(2):425–438. doi:10.1681/asn.2013111156

    Article  PubMed  CAS  Google Scholar 

  277. Maguire D, MacNamara B, Cuffe JE, Winter D, Doolan CM, Urbach V, O’Sullivan GC, Harvey BJ (1999) Rapid responses to aldosterone in human distal colon. Steroids 64(1–2):51–63

    Article  CAS  PubMed  Google Scholar 

  278. McNamara B, Winter DC, Cuffe JE, O’Sullivan GC, Harvey BJ (1999) Basolateral K(+) channel involvement in forskolin-activated chloride secretion in human colon. J Physiol 519(Pt 1):251–260. doi:10.1111/j.1469-7793.1999.0251o.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Harvey BJ, Doolan CM, Condliffe SB, Renard C, Alzamora R, Urbach V (2002) Non-genomic convergent and divergent signalling of rapid responses to aldosterone and estradiol in mammalian colon. Steroids 67(6):483–491. doi:10.1016/S0039-128X(01)00169-6

    Article  CAS  PubMed  Google Scholar 

  280. Doolan CM, Harvey BJ (1996) Modulation of cytosolic protein kinase C and calcium ion activity by steroid hormones in rat distal colon. J Biol Chem 271(15):8763–8767

    Article  CAS  PubMed  Google Scholar 

  281. Martin RS, Oszi P, Brocca S, Arrizurieta E, Hayslett JP (1986) Failure of potassium adaptation in vivo in the colon of aldosterone-deficient rats. J Lab Clin Med 108(3):241–245

    CAS  PubMed  Google Scholar 

  282. Sorensen MV, Matos JE, Praetorius HA, Leipziger J (2010) Colonic potassium handling. Pflugers Arch 459(5):645–656. doi:10.1007/s00424-009-0781-9

    Article  CAS  PubMed  Google Scholar 

  283. Sorensen MV, Strandsby AB, Larsen CK, Praetorius HA, Leipziger J (2011) The secretory KCa1.1 channel localises to crypts of distal mouse colon: functional and molecular evidence. Pflugers Arch 462(5):745–752. doi:10.1007/s00424-011-1000-z

    Article  CAS  PubMed  Google Scholar 

  284. Christ M, Sippel K, Eisen C, Wehling M (1994) Non-classical receptors for aldosterone in plasma membranes from pig kidneys. Mol Cell Endocrinol 99(2):R31–R34

    Article  CAS  PubMed  Google Scholar 

  285. Meyer C, Christ M, Wehling M (1995) Characterization and solubilization of novel aldosterone-binding proteins in porcine liver microsomes. Eur J Biochem 229(3):736–740

    Article  CAS  PubMed  Google Scholar 

  286. Eisen C, Meyer C, Christ M, Theisen K, Wehling M (1994) Novel membrane receptors for aldosterone in human lymphocytes: a 50 kDa protein on SDS-PAGE. Cell Mol Biol (Noisy-le-grand) 40(3):351–358

    CAS  Google Scholar 

  287. Losel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M (2003) Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 83(3):965–1016. doi:10.1152/physrev.00003.2003

    Article  PubMed  Google Scholar 

  288. Alzamora R, Michea L, Marusic ET (2000) Role of 11beta-hydroxysteroid dehydrogenase in nongenomic aldosterone effects in human arteries. Hypertension 35(5):1099–1104

    Article  CAS  PubMed  Google Scholar 

  289. Krug AW, Pojoga LH, Williams GH, Adler GK (2011) Cell membrane-associated mineralocorticoid receptors? New evidence. Hypertension 57(6):1019–1025. doi:10.1161/HYPERTENSIONAHA.110.159459

    Article  CAS  PubMed  Google Scholar 

  290. Barton M, Meyer MR (2015) Nicolaus Copernicus and the rapid vascular responses to aldosterone. Trends Endocrinol Metab 26(8):396–398. doi:10.1016/j.tem.2015.05.005

    Article  CAS  PubMed  Google Scholar 

  291. Feldman RD, Limbird LE (2015) Copernicus revisited: overturning Ptolemy’s view of the GPER universe. Trends Endocrinol Metab 26(11):592–594. doi:10.1016/j.tem.2015.09.002

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Pablo Henrique Oliveira de Silva for extensively revising the manuscript. H.M.M is a fellow of CAPES; de Assis, L.V.M is a fellow of FAPESP (2013/24337-4). These authors contributed equally to this work. Our lab is funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq.

Author information

Authors and Affiliations

  1. Laboratory of Hypertension, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Campus Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil

    Milla Marques Hermidorff & Mauro César Isoldi

  2. Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil

    Leonardo Vinícius Monteiro de Assis

Authors
  1. Milla Marques Hermidorff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonardo Vinícius Monteiro de Assis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mauro César Isoldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mauro César Isoldi.

Ethics declarations

Our lab is funded by FAPEMIG (APQ-02112-10 and APQ 00793-13) and CNPq. H.M.M is a fellow of CAPES; de Assis, L.V.M is a fellow of FAPESP (2013/24337-4). Author Milla Marques Hermidorff declares no conflict of interest; Author Leonardo V.M. de Assis declares no conflict of interest; Mauro César Isoldi declares no conflict of interest. This article does not contain any studies with human or animal participants performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

We also state that all research funding for our laboratory is originated from State and Federal Programs and not from the private sector.

Additional information

Milla Marques Hermidorff and Leonardo Vinícius Monteiro de Assis contributed equally for this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hermidorff, M.M., de Assis, L.V.M. & Isoldi, M.C. Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Fail Rev 22, 65–89 (2017). https://doi.org/10.1007/s10741-016-9591-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-016-9591-2

Keywords

Search

Navigation