Human Mineralocorticoid Receptor Expression Renders Cells Responsive for Nongenotropic Aldosterone Actions

Großmann, Claudia; Benesic, Andreas; Krug, Alexander W.; Freudinger, Ruth; Mildenberger, Sigrid; Gaßner, Birgit; Gekle, Michael

doi:10.1210/me.2004-0469

Cited by 163 publications

(148 citation statements)

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“…Knowledge of the crosstalk between genomic and nongenotropic actions will be critical for our understanding the diverse biologic responses to steroids. 7 In our heterologous MR expression system (Grossmann et al, 2005) inhibition of ERK1/2 reduced aldosterone-induced transactivation activity at a canonical GRE element. The underlying mechanisms included impaired nuclear-cytoplasmic shuttling of MR.…”

Section: Accepted Manuscriptmentioning

confidence: 97%

“…To test the hypothesis of aldosterone/MR-induced EGFR transactivation further we employed a heterologous expression system (Grossmann et al, 2005). In cells without detectable expression of MR either functionally (GRE-reporter assay) or on the mRNA and protein level (CHO cells, HEK cells), aldosterone elicited no response with respect to ERK1/2 activation (Grossmann et al, 2005; Krug et al, 2002).…”

Section: Confirmation Of Aldosterone-induced Egfr Transactivation Andmentioning

confidence: 99%

“…In cells without detectable expression of MR either functionally (GRE-reporter assay) or on the mRNA and protein level (CHO cells, HEK cells), aldosterone elicited no response with respect to ERK1/2 activation (Grossmann et al, 2005; Krug et al, 2002). After transfection with the human MR, the cells showed a genomic response to aldosterone as well as rapid activation of the kinases ERK1/2 and JNK (Grossmann et al, 2005). Aldosterone induced ERK1/2 activation was prevented by two different pharmacological inhibitors of EGFR kinase, AG1478 and AG112, and by the MR antagonist spironolactone.…”

Section: Confirmation Of Aldosterone-induced Egfr Transactivation Andmentioning

confidence: 99%

“…This mechanism is also of potential importance for pathophysiological effects of activated MR because (i) EGFR has been shown to promote pathological tissue alterations and (ii) because activated MR enhances the number of switches for angiotensin II and endothelin-1. So far, at least three tracks of cellular aldosterone signaling have been described and therefore have to be considered (Grossmann et al, 2005). Besides the classical, MR-dependent, genomic track, leading to the expression of so-called aldosterone-induced proteins like the EGFR, we have a rapid, nongenotropic but MR-dependent track, leading to the activation of, at least, ERK1/2-and JNK1/2-kinase.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Finally, there is an ill-defined nongenotropic, MR-independent track, which nevertheless seems to distinguish between aldosterone and dexamethasone but does not seem to involve the EGFR. There are indications that aldosterone enhances Ca 2+ -influx by a yet unknown pathways through this mechanism (Grossmann et al, 2005;Gekle et al, 1996). What is still not clear is if these different signaling pathways interact with each other.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Non-classical actions of the mineralocorticoid receptor: Misuse of EGF receptors?

Großmann

Gekle²

2007

Molecular and Cellular Endocrinology

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The mineralocorticoid receptor (MR) plays a key role in cardiovascular and renal injury. The underlying mechanisms seem to involve the epidermal growth factor receptor (EGFR) for the development of fibrosis and vascular dysfunction. Both enhanced EGFR transactivation by activated MR as well as upregulation of EGFR expression by aldosterone-bound MR have been described. While the former seems to be mediated by the tyrosine kinase cSrc, reporter gene assays and chromatin immunoprecipitation data indicate that the latter is caused by an interaction between MR and the EGFR promoter. Pharmacological inhibition of EGFR function prevents some of MR´s pathological actions in cell culture systems, like vascular smooth muscle cells. Thus, transactivation as well as enhanced expression of EGFR may be an important switch for the pathophysiological actions in the reno-cardiovascular continuum. Furthermore, EGFR signaling may serve as a negative feedback loop to limit sodium retention. Overall, MR´s "misuse" of the EGFR is one possible explanation for the pathophysiological effects of aldosterone, making the EGFR a potential target for therapeutical interventions against reno-cardiovascular remodelling. Page 3 of 15A c c e p t e d M a n u s c r i p t Non-classical actions of aldosterone and EGFR 3 Classical and non-classical effects of the mineralocorticoid receptor and aldosteroneAldosterone is a steroid hormone and the main mineralocorticoid in humans. It is secreted by the zona glomerulosa of the adrenal cortex and for a long time was thought to be primarily involved in electrolyte and volume homeostasis. These classical actions of aldosterone have been mostly studied in the distal nephron and collecting duct of the kidney in the so-called principal cells, responsible for sodium reabsorption and potassium secretion. Aldosterone enters the principal cells presumably by diffusion and bind to its receptor, the mineralocorticoid receptor (MR), located mainly in the cytosol tethered to a heteromeric complex containing hsp90 and other chaperone molecules (Arriza et al., 1987;. Upon hormone binding, the MR dissociates from this complex, forms homodimers and translocates to the nucleus where it acts as a ligand-induced transcription factor, binding to response elements and modulating the expression of aldosterone-sensitive genes. So far, no mineralocorticoid receptor specific promoter elements have been described and the only binding sites known are shared between the glucocorticoid receptor and the mineralocorticoid receptor and are therefore called glucocorticoid response elements (GRE). In the case of principal cells, the epithelial sodium channel (ENaC), potassium channel ROMK, Na + /K + -ATPase and mitochondrial enzymes are known targets of MR regulation. The cellular response -sodium reabsorption and potassium secretion eventually leads to systemic alterations, like salt and water retention, enhanced blood pressure, hypokalemia and alkalosis. Similar mechanisms of action also occur in other tight epithelia, like the ...

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Section: Accepted Manuscriptmentioning

confidence: 97%

Section: Confirmation Of Aldosterone-induced Egfr Transactivation Andmentioning

confidence: 99%

Section: Confirmation Of Aldosterone-induced Egfr Transactivation Andmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

See 3 more Smart Citations