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

Abstract

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 ...

Aldosterone Activates NF-κB in the Collecting Duct

“…On the basis of the observation that many genes regulated by MAPK are also controlled by NF-B, some studies have demonstrated that activation of p38 kinase and ERK pathways enhance the transactivation potential of p65/RelA. 29 Aldosterone activates MAPK through various mechanisms, including MR-dependent transactivation of the EGF receptor, 5 or redox-sensitive pathways. 6 Nevertheless, we found that several hours of aldosterone treatment did not alter the phosphorylation levels of ERK1/2 and decreased phosphorylation of p38 kinase, suggesting that the activity of these MAPK is unaltered or decreased, respectively.…”

“…[1][2][3][4] Activation of the EGF receptor and mitogen-activated protein kinases (MAPK), induction of oxidative stress, and MR-dependent transcription of proinflammatory genes are some of the mechanisms proposed to account for the injurious effects induced by aldosterone. [5][6][7][8] As outlined by recent reports, mineralocorticoid also mediates inflammation and fibrosis through NF-B activation in liver, heart, and glomerular mesangial cells 9 -13 via a pathway involving the aldosterone early-induced gene, serum and glucocorticoid-induced kinase 1 (SGK1). 11,12 NF-B is a transcription factor composed of dimers of Rel family proteins (p65/RelA, p50/p105, p52/p100, RelB, and c-Rel).…”

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

“…11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have been demonstrated after aldo stimulation, ex vivo after the incubation of rat aorta and renal, endothelial, and vascular smooth muscle cultured cells with aldo and in vivo in the aorta of adrenalectomized rats treated with aldo. [13][14][15][16] However, the consequences of EFGR activation to the vascular effects of aldo have not yet been demonstrated in vivo.…”

Mineralocorticoid and Epidermal Growth Factor Receptors

“…One confounder may be that many studies, particularly those examining the coronary vasculature, use a longer period of mineralocorticoid/salt treatment, that is, 8 weeks. 6,7 Although these results may be interpreted as evidence that the in vitro studies 10 have not recapitulated the in vivo situation, there are the usual caveats. In any germline knockout mouse, the possibility that there is redundancy and/or compensatory mechanisms (which may be recruited during development) must be considered.…”

“…This response appears to involve MR, but not in a classic genomic pathway; the activation involves the cytosolic tyrosine kinase cSrc, which is known to activate EGFR. 10 Activation of the EGFR and its downstream effectors, such as extracellular signal-regulated kinase, is proliferative, and, indeed, the effects of angiotensin on extracellular signalregulated kinase activity also involve the EGFR. GriolCharhbili et al 9 seek to directly address the role of the EGFR in mediating mineralocorticoid/salt-induced vascular damage in vivo.…”