Rapid Nongenomic Effects of Aldosterone in Mineralocorticoid-Receptor-Knockout Mice

Haseroth, K.; Gerdes, Dirk; Berger, Stefan; Feuring, Martin; Günther, Andreas; Herbst, Curt; Christ, Michael; Wehling, Martin

doi:10.1006/bbrc.1999.1771

Cited by 128 publications

(96 citation statements)

References 24 publications

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“…Our data add to the growing literature describing rapid, nongenomic effects of aldosterone (2,5,(32)(33)(34)(35). For example, aldosterone activates signaling pathways such as PKA, PKC, PKD, MAPK, and the NADPH oxidase in vascular smooth muscle; and aldosterone activates phosphatidylinositol 3-kinase in endothelial cells (32,34,(36)(37)(38)(39)(40)(45)(46)(47). However, nongenomic effects of aldosterone can be mediated through either the MR or other unidentified proteins.…”

Section: Aldosterone Activates Endothelial Exocytosis Through a Nongementioning

confidence: 58%

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Aldosterone activates endothelial exocytosis

Jeong¹,

Chaupin²,

Matsushita³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although elevated levels of aldosterone are associated with vascular inflammation, the proinflammatory pathways of aldosterone are not completely defined. We now show that aldosterone triggers endothelial cell exocytosis, the first step in leukocyte trafficking. Exogenous aldosterone stimulates endothelial exocytosis of Weibel-Palade bodies, externalizing P-selectin and releasing von Willebrand factor. Spironolactone, a nonselective mineralocorticoid receptor (MR) blocker, antagonizes aldosterone-induced endothelial exocytosis. Knockdown of the MR also decreases exocytosis, suggesting that the MR mediates exocytosis. Aldosterone triggers exocytosis within minutes, and this effect is not inhibited by actinomycin D, suggesting a nongenomic effect of aldosterone. Aldosterone treatment of endothelial cells increases leukocyte adherence to endothelial cells in culture. Taken together, our data suggest that aldosterone activates vascular inflammation in part through nongenomic, MR-mediated pathways. Aldosterone antagonism may decrease vascular inflammation and cardiac fibrosis in part by blocking endothelial exocytosis.inflammation ͉ mineralocorticoid ͉ P-selectin ͉ vascular ͉ nitric oxide

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Section: Aldosterone Activates Endothelial Exocytosis Through a Nongementioning

confidence: 58%

“…Aldosterone rapidly activates mitogen-activated protein kinase (MAPK) signaling in fibroblasts (36,37). Furthermore, aldosterone rapidly activates calcium influx and protein kinase C (PKC), cAMP levels and protein kinase A (PKA), and protein kinase D (PKD) signaling pathways (32,34,(38)(39)(40).…”

mentioning

confidence: 99%

Aldosterone activates endothelial exocytosis

Jeong¹,

Chaupin²,

Matsushita³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Of interest, a rapid intracellular Ca 2ϩ flux in response to aldosterone was retained in the keratinocytes of MR knockout mice, leading to the possibility that there are distinct receptors for rapid signaling and indicating further levels of complexity in MR signaling. 56 Rapid responses blocked by MR antagonist spironolactone or potassium canrenoate indicate signaling via the classic MR. Those thus far described include interactions with the epidermal growth factor signaling pathway, which results in rapid dose-dependent phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 kinases. 57,58 Similarly, in rabbit cardiomyocytes, aldosterone increases Naϩ/Kϩ pump activity via direct activation of the Na ϩ /K ϩ /2Cl -cotransporter.…”

Section: Rapid Nongenomic Mechanisms: Signaling Through the Mrmentioning

confidence: 99%

Mechanisms of Mineralocorticoid Action

Fuller¹,

Young²

2005

Hypertension

280

169

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Abstract-Sodium transport in epithelial tissues is regulated by the physiological mineralocorticoid aldosterone. The response to aldosterone is mediated by the mineralocorticoid receptor (MR), for which the crystal structure of the ligand-binding domain has recently been established. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have now been shown to be regulated by aldosterone in epithelial tissues. Of these, the best characterized is serum-and glucocorticoid-regulated kinase, which increases sodium influx through the epithelial sodium channel. Turnover of these channels in the cell membrane is mediated by Nedd4 -2, a ubiquitin protein ligase; serum-and glucocorticoid-regulated kinase interacts with and phosphorylates Nedd4 -2, thereby rendering it unable to bind the sodium channels. Key Words: aldosterone Ⅲ sodium channels Ⅲ fibrosis T he isolation of aldosterone just over 50 years ago established it as the primary physiological mineralocorticoid. 1 Sodium transport, and hence salt balance, is regulated by a number of mechanisms; however, aldosterone has a critical role. Aldosterone exerts its effects on the distal nephron (and colon) as the last point of sodium reabsorption; it is thus the final arbiter. 2,3 The importance of aldosterone in the maintenance of sodium homeostasis is seen in a series of monogenetic causes of hypertension, 2 in Conn's syndrome, and in disorders in which mineralocorticoid action is compromised with consequent, life-threatening salt losses. 3 Although other pathophysiological consequences of aldosterone excess were identified by Selye 4 over 60 years ago, their significance has only recently been appreciated. Evidence from the Randomized ALdactone Evaluation Study (RALES) and EPlerenone neuroHormonal Efficacy and SUrvival Study (EPHESUS) trials of beneficial effects of mineralocorticoid antagonist therapy on morbidity and mortality in cardiac failure has focused attention beyond the kidney to effects of mineralocorticoids more broadly in the cardiovascular system. 5 Although an understanding of the molecular basis of aldosterone action has tended to lag behind advances in the biology of other steroid hormones, the last decade has seen significant advances toward an understanding of the mechanisms of mineralocorticoid action. The primary mediator of the response to aldosterone is the mineralocorticoid receptor (MR), the ligand-binding domain (LBD) of which has been recently crystallized. 6 -8 Although the MR primarily acts as a transcription factor, recent evidence suggests that it may also mediate nongenomic (or nonnuclear) activation of second messenger pathways. In addition, there is a growing body of evidence that some actions of aldosterone may involve a receptor other than the MR. The cellular and molecular mediators, including proteins induced by aldosterone, have been characterized in sodium transporting epithelia; however, the critical molecular events in the vasculature remain to be determined. In this brief r...

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“…On the basis of several lines of evidence [254][255][256][257], it has been proposed that non-genomic ALDO actions i) are mediated by a distinct and specific membrane receptor that is different from the classical intracellular MR, ii) are insensitive to classical MR antagonists, such as canrenone or spironolactone, iii) are based on a high affinity for ALDO but not for glucocorticoids. The physiological and clinical relevance supporting these rapid effects remains unclear, but their existence has been described in various target organs and cells, including amphibian skin and urinary bladders [258,259], vascular smooth muscle cells and endothelial cells [260], skeletal muscle cells [261], human mononuclear leukocytes [262], cardiac myocytes [263], skin fibroblasts from MR-knockout mice [256], colonic epithelial cells [264] and isolated colonic crypts [265]. Several sites in the kidney, particularly cultured kidney cells, have been shown to be sensitive to non-genomic ALDO action [266], including principal cells that were freshly isolated from rabbits [267], the human distal colon [268], in vivo renal proximal tubules (S2 segment) [228], isolated renal proximal tubules (S3 segment) [229,233], medullary thick ascending limbs [269] and renal collecting duct cells [270].…”

Section: Non-genomic Actions Of Aldomentioning

confidence: 99%

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Mello-Aires¹,

Dellova²,

Castelo‐Branco³

et al. 2017

Nephrol Renal Dis

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This article reviews the main body of knowledge regarding NHE1 and NHE3 exchangers and their interaction with Angiotensin II, Angiotensin-(1-7), Aldosterone and Arginine Vasopressin, particularly their renal actions. This work addresses the biphasic effects of different hormonal doses on NHE1 or NHE3 in proximal tubule in Wistar, SHR (hypertensives) and their control WKY (normotensives) rats or MDCK cells (which share similarities with the collecting duct). The hormones were applied alone, with their inhibitors or plus agents that change the [Ca 2+ ]i. The data are compatible with hormonal stimulation of these exchangers by increases of [Ca 2+ ]i in lower range, and inhibition at high [Ca 2+ ]i. In MDCK cells and Wistar rats, low doses of ANG II, ALDO or AVP stimulated the exchangers, while high doses inhibited them. ANG-(1-7), in Wistar or WKY rats has inverse, dose-dependent effects. In SHR rats, the biphasic effects of ANG-(1-7) were similar to the effects of ANG II, ALDO or AVP in Wistar rats. The interactions between these effects may represent a mechanism that regulates extracellular volume. In hypertensives animals, a high plasma level of ANG-(1-7) inhibited NHE3 in the proximal tubule, which mitigated hypertension. Figure 6 shows a schematic model to describe these biphasic hormonal effects.

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Rapid Nongenomic Effects of Aldosterone in Mineralocorticoid-Receptor-Knockout Mice

Cited by 128 publications

References 24 publications

Aldosterone activates endothelial exocytosis

Aldosterone activates endothelial exocytosis

Mechanisms of Mineralocorticoid Action

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

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