Aldosterone Stimulates Epidermal Growth Factor Receptor Expression

The steroid hormone aldosterone plays an important role during pathological tissue modifications, similar to cardiovascular or renal fibrosis. The underlying mechanisms for the pathological actions are not understood. Interaction of aldosterone with the epidermal growth factor (EGF) receptor is an attractive hypothesis to explain pathological tissue remodeling elicited by aldosterone, because (i) mineralocorticoids can sensitize cells for EGF, (ii) mineralocorticoid receptor (MR)-antagonists reduce EGFR-mRNA expression, (iii) EGFR itself supports the development of cardiovascular or renal fibrosis, and (iv) signaling elements involved in the pathological action of aldosterone (similar to ERK1/2 or NFkB) are typical downstream modules during EGF signaling. In addition, an interaction of aldosterone and EGF with respect to ERK1/2 activation has been described. Here we show that aldosterone stimulates EGFR expression in renal tissue of adrenalectomized rats and in human renal primary cell cultures. Furthermore, Chinese hamster ovary (CHO) cells normally devoid of EGFR or MR express EGFR after transfection with human MR (CHO-MR cells) but not after transfection with human glucocorticoid receptor (CHO-GR cells). In CHO-MR cells, EGFR-expression is up-regulated by aldosterone and inhibited by spironolactone. CHO-MR cells but not CHO-GR cells respond with ERK1/2 phosphorylation to EGF exposure. The responsiveness to other peptide hormones was virtually not affected. These data suggest that EGFR is an aldosterone-induced protein and is involved in the manifold (patho)biological actions of aldosterone. The steroid hormone aldosterone plays an important role during pathological tissue modifications, similar to cardiovascular or renal fibrosis. The underlying mechanisms for the pathological actions are not understood. Interaction of aldosterone with the epidermal growth factor (EGF) receptor is an attractive hypothesis to explain pathological tissue remodeling elicited by aldosterone, because (i) mineralocorticoids can sensitize cells for EGF, (ii) mineralocorticoid receptor (MR)-antagonists reduce EGFR-mRNA expression, (iii) EGFR itself supports the development of cardiovascular or renal fibrosis, and (iv) signaling elements involved in the pathological action of aldosterone (similar to ERK1/2 or NFkB) are typical downstream modules during EGF signaling. In addition, an interaction of aldosterone and EGF with respect to ERK1/2 activation has been described. Here we show that aldosterone stimulates EGFR expression in renal tissue of adrenalectomized rats and in human renal primary cell cultures. Furthermore, Chinese hamster ovary (CHO) cells normally devoid of EGFR or MR express EGFR after transfection with human MR (CHO-MR cells) but not after transfection with human glucocorticoid receptor (CHO-GR cells). In CHO-MR cells, EGFR-expression is up-regulated by aldosterone and inhibited by spironolactone. CHO-MR cells but not CHO-GR cells respond with ERK1/2 phosphorylation to EGF exposure. The responsiveness to other peptide hormones was virtually not affected. These data suggest that EGFR is an aldosterone-induced protein and is involved in the manifold (patho)biological actions of aldosterone. Nowadays, it is evident that the importance, especially the pathophysiological importance, of aldosterone and the mineralocorticoid receptor extends beyond the regulation of salt and water homeostasis. Most importantly, it has been demonstrated that aldosterone promotes cardiovascular and renal fibrosis because of tissue remodeling as well as endothelial dysfunction independent of its effects on blood pressure or salt homeostasis (1Funder J. Clin. Exp. Pharmacol. Physiol. 2001; 28: 1002-1006Crossref PubMed Scopus (74) Google Scholar, 2Epstein M. Am. J. Kidney Dis. 2001; 37: 677-688Abstract Full Text PDF PubMed Scopus (141) Google Scholar, 3Epstein M. J. R. Soc. Med. 2001; 94: 378-383Crossref PubMed Scopus (62) Google Scholar, 4Bauersachs J. Heck M. Fraccarollo D. Hildemann S.K. Ertl G. Wehling M. J. Am. Coll. Cardiol. 2002; 39: 351-358Crossref PubMed Scopus (140) Google Scholar, 5Blasi E.R. Rocha R. Rudolph A.E. Blomme E.A. Polly M.L. McMahon E.G. Kidney Int. 2003; 63: 1791-1800Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar). Several mechanisms have been proposed for the pathological actions of aldosterone, including enhanced collagen and fibronectin synthesis, stimulation of reactive oxygen species formation, decreased nitric oxide availability, and enhanced expression of peptide hormones (e.g. endothelin-1) or their receptors (e.g. AT1-receptor) (2Epstein M. Am. J. Kidney Dis. 2001; 37: 677-688Abstract Full Text PDF PubMed Scopus (141) Google Scholar, 6Lijnen P. Petrov V. J. Mol. Cell Cardiol. 2000; 32: 865-879Abstract Full Text PDF PubMed Scopus (223) Google Scholar). The pathophysiological role of aldosterone has received impressive support from clinical studies, especially the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infaction Heart Failure Efficacy and Survival Study. Low doses of mineralocorticoid receptor antagonists led to a dramatic improvement of mortality in patients with severe congestive heart failure or after myocardial infarction (7Pitt B. Zannad F. Remme W.J. Cody R. Castaigne A. Perez A. Palensky J. Wittes J. N. Engl. J. Med. 1999; 341: 709-717Crossref PubMed Scopus (7845) Google Scholar, 8Pitt B. Remme W. Zannad F. Neaton J. Martinez F. Roniker B. Bittman R. Hurley S. Kleiman J. Gatlin M. N. Engl. J. Med. 2003; 348: 1309-1321Crossref PubMed Scopus (4258) Google Scholar). Thus, it is clear that aldosterone exerts important non-classical, non-epithelial actions. Unfortunately, the underlying mechanisms of this important action of aldosterone and the mineralocorticoid receptor are only poorly understood. Classically, aldosterone binds to the cytosolic mineralocorticoid receptor (MR) 1The abbreviations used are: MR, mineralocorticoid receptor; ADX, adrenalectomized; Aldo, aldosterone; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; GR, glucocorticoid receptor; PMA, phorbol 12-myristate 13-acetate; MDCK, Madin-Darby canine kidney cells; PBS, phosphate-buffered saline; Luc, luciferase; ANOVA, analysis of variance; hMR, human MR; hGR, human GR; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. (9Arriza J.L. Weinberger C. Cerelli G. Glaser T.M. Handelin B.L. Housman D.E. Evans R.M. Science. 1987; 237: 268-275Crossref PubMed Scopus (1703) Google Scholar), which then translocates to the cell nucleus and acts as a transcription factor. Subsequently, the expression of various proteins like the epithelial sodium channel, the Na+-K+-ATPase, or the serum and glucocorticoid-regulated kinase is modulated (9Arriza J.L. Weinberger C. Cerelli G. Glaser T.M. Handelin B.L. Housman D.E. Evans R.M. Science. 1987; 237: 268-275Crossref PubMed Scopus (1703) Google Scholar, 10Bonvalet J.-P. Kidney Int. 1998; 53: S49-S56Google Scholar, 11Verrey F. Pearce D. Pfeiffer R. Spindler B. Mastroberardino L. Summa V. Zecevic M. Kidney Int. 2000; 57: 1277-1282Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 12Verrey F. Am. J. Physiol. 1999; 277: F319-F327Crossref PubMed Google Scholar, 13Eaton D.C. Malik B. Saxena N.C. Al-Khalili O.K. Yue G. J. Membr. Biol. 2001; 184: 313-319Crossref PubMed Scopus (83) Google Scholar, 14Stockand J.D. Am. J. Physiol. 2002; 282: F559-F576Crossref PubMed Scopus (168) Google Scholar). It has been proposed that the transcription factors NFkB and AP1 as well as the mitogen-activated kinases ERK1/2 are involved in the pathological actions of aldosterone (15Fiebeler A. Schmidt F. Muller D.N. Park J.K. Dechend R. Bieringer M. Shagdarsuren E. Breu V. Haller H. Luft F.C. Hypertension. 2001; 37: 787-793Crossref PubMed Google Scholar, 16Stockand J.D. Meszaros J.G. Am. J. Physiol. 2003; 284: H176-H184Crossref PubMed Scopus (159) Google Scholar, 17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). However, these signaling pathways are usually associated with growth factors or cytokine receptors rather than with aldosterone signaling. In this respect, it is of interest that steroids, including aldosterone, have the ability to interact with peptide hormone signaling (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). One important peptide signaling “system” with respect to aldosterone is the epidermal growth factor (EGF) and its receptor (EGFR) (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 18Gekle M. Freudinger R. Mildenberger S. Silbernagl S. Am. J. Physiol. 2002; 282: F669-F679Crossref PubMed Scopus (72) Google Scholar). Pharmacological in vivo studies have shown that mineralocorticoids enhance EGF-induced contraction of arteries (19Florian J.A. Dorrance A. Webb R.C. Watts S.W. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001; 281: R878-R886Crossref PubMed Google Scholar) and that the MR-antagonist spironolactone reduces the expression of EGFR-mRNA after cerebral ischemia (20Dorrance A.M. Osborn H.L. Grekin R. Webb R.C. Am. J. Physiol. 2001; 281: R944-R950PubMed Google Scholar). Furthermore, EGFR expression supports fibrosis in cardiovascular and renal tissue (21Terzi F. Burtin M. Hekmati M. Federici P. Grimber G. Briand P. Friedlander G. J. Clin. Invest. 2000; 106: 225-234Crossref PubMed Scopus (161) Google Scholar, 22Flamant M. Tharaux P.L. Placier S. Henrion D. Coffman T. Chatziantoniou C. Dussaule J.C. FASEB J. 2003; 17: 327-329Crossref PubMed Scopus (75) Google Scholar, 23Kagiyama S. Qian K. Kagiyama T. Phillips M.I. Hypertension. 2003; 41: 824-829Crossref PubMed Scopus (64) Google Scholar). The importance of the EGFR in mediating pathophysiological effects of heterologous signaling systems is supported by its role in endothelin-induced fibrogenic effects (22Flamant M. Tharaux P.L. Placier S. Henrion D. Coffman T. Chatziantoniou C. Dussaule J.C. FASEB J. 2003; 17: 327-329Crossref PubMed Scopus (75) Google Scholar). Endothelin-induced phosphorylation of the mitogen-activated protein kinase and endothelin-induced increase in collagen I gene activity were completely prevented by an inhibitor of the EGFR kinase. Thus, EGFR does not only transduce the signal of its classical ligand EGF but also serves as a heterologous transducer for other signaling pathways (24Hackel P.O. Zwick E. Prenzel N. Ullrich A. Curr. Opin. Cell Biol. 1999; 11: 184-189Crossref PubMed Scopus (549) Google Scholar, 25Moghal N. Sternberg P.W. Curr. Opin. Cell Biol. 1999; 11: 190-196Crossref PubMed Scopus (290) Google Scholar) including glucocorticoids, aldosterone, and estrogen. The steroids modulate EGFR activity and the downstream signaling modules (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 18Gekle M. Freudinger R. Mildenberger S. Silbernagl S. Am. J. Physiol. 2002; 282: F669-F679Crossref PubMed Scopus (72) Google Scholar, 26Croxtall J.D. Choudhury Q. Flower R.J. Br. J. Pharmacol. 2000; 130: 289-298Crossref PubMed Scopus (275) Google Scholar, 27Kelly M.J. Levin E.R. Trends Endocrinol. Metab. 2001; 12: 152-156Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 28Gekle M. Freudinger R. Mildenberger S. Silbernagl S. Steroids. 2002; 67: 499-504Crossref PubMed Scopus (37) Google Scholar). Besides modulating the EGFR activity, the steroids also influence the expression of the EGFR. Factors like AP1, protein kinase C, cAMP, thyroxin, and vitamin D3 stimulate EGFR expression whereas estrogen inhibits it (29Yarden Y. Sliwkowski M.X. Nat. Rev. Mol. Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (5772) Google Scholar, 30Nishi H. Senoo M. Nishi K.H. Murphy B. Rikiyama T. Matsumura Y. Habu S. Johnson A.C. J. Biol. Chem. 2001; 276: 41717-41724Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 31Johnson A.C. J. Biol. Chem. 1996; 271: 3033-3038Abstract Full Text Full Text PDF PubMed Google Scholar, 32Johnson A.C. Murphy B.A. Matelis C.M. Rubinstein Y. Piebenga E.C. Akers L.M. Neta G. Vinson C. Birrer M. Mol. Med. 2000; 6: 17-27Crossref PubMed Google Scholar, 33Kageyama R. Merlino G.T. Pastan I. J. Biol. Chem. 1989; 264: 15508-15514Abstract Full Text PDF PubMed Google Scholar, 34Rubinsetin Y.R. Proctor K.N. Bergel M. Murphy B. Johnson A.C. FEBS Lett. 1998; 431: 268-272Crossref PubMed Scopus (18) Google Scholar). In most cases, the underlying mechanisms are only poorly understood. This study was designed to investigate the effect of aldosterone and the MR on EGFR expression. Animal Study—Male Munich-Wistar rats weighing between 250 and 350 g (Charles River, Sulzfeld, Germany) underwent adrenalectomy or sham operation under NarcorenR anesthesia using two lumbodorsal incisions. Aldosterone (ADX+aldo) (36 μg/100 g body weight and day) or vehicle (ADX) was applied by osmotic mini-pumps The adrenalectomized were on in of water and on a M. H. K. J. Physiol. Scopus Google Scholar, A.W. F. Ullrich Gekle M. 2003; PubMed Scopus Google Scholar). The of adrenalectomy and the of aldosterone by osmotic were by of aldosterone and the aldosterone in was and in The was in and in after the were with body the were and the was with of a Germany) was to R.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). Subsequently, of protein were to and as Cell cells from were as (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 18Gekle M. Freudinger R. Mildenberger S. Silbernagl S. Am. J. Physiol. 2002; 282: F669-F679Crossref PubMed Scopus (72) Google Scholar). were in with serum and to the serum was from the the the cells were on or in cells of human kidney were from and to the and of the cells was with the Germany) to the used the expression N. B. T. J. Ullrich A. Mol. Cell Biol. 12: PubMed Scopus Google Scholar), the expression the expression M. Freudinger R. Mildenberger S. Silbernagl S. Am. J. Physiol. 2002; 282: F669-F679Crossref PubMed Scopus (72) Google Scholar), and H. PubMed Scopus Google Scholar), which a gene of was with by their or expression was by and their EGF receptor expression was by were with phosphate-buffered and in sodium or for Cell were for protein by and to a Subsequently, were with or The primary was using and the were with with PBS, and with Subsequently, cells were for in by of and for in serum with the cells were with and for with the cells were to the of an and were using a of ERK1/2 by of ERK1/2 phosphorylation was by to E. M. J. 2000; PubMed Scopus Google Scholar) with (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). were in and for to the stimulation as in the the cells were with in and with were with serum in for and with the primary cells were with the in with serum for and with for and with Subsequently, the cells were with of a and in the The signal was with a protein in the was with (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). and was using the and was using M. P. P. J. PubMed Scopus Google Scholar). was using the from was using the from was by The were MR MR MR MR and EGFR under the of the EGFR was by A. Johnson of H. Senoo M. Nishi K.H. Murphy B. Rikiyama T. Matsumura Y. Habu S. Johnson A.C. J. Biol. Chem. 2001; 276: 41717-41724Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). were with and the to transfection activity was using the and was using the activity was for and the were from of the other were from was of and the or data are as of was by or or as were from two were used for the of cell or tissue we aldosterone to adrenalectomized rats EGFR expression. this we kidney that the of aldosterone in an enhanced expression of EGFR. The serum of aldosterone was in the to pathophysiological of aldosterone but was to two of the of show that aldosterone stimulates EGFR expression in most the the in vivo data are not and studies have to investigate in and the effects of aldosterone to of and spironolactone MR from other have for a action of aldosterone on EGFR expression (19Florian J.A. Dorrance A. Webb R.C. Watts S.W. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001; 281: R878-R886Crossref PubMed Google Scholar, A.M. Osborn H.L. Grekin R. Webb R.C. Am. J. Physiol. 2001; 281: R944-R950PubMed Google Scholar). of protein expression can because (i) of protein were for and (ii) because we have shown in a study A.W. F. Ullrich Gekle M. 2003; PubMed Scopus Google Scholar) that expression is not by the In a we used human kidney cells to is a effect of aldosterone on human and analysis for the expression of MR in the cells of aldosterone in a similar as in the in vivo study led to an EGFR expression Thus, the in vivo data in a primary cell of human data that aldosterone stimulates EGFR expression the MR, we to a heterologous expression of cells with or This has the of well and the of not However, for the the that cells, which not express EGFR or MR and are not to EGF under (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), express EGFR after transfection with human MR (CHO-MR cells) but not after transfection with the in This was in CHO-MR cell and and The expression of EGFR also by and was in EGFR cells with human (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) or with human Thus, not only estrogen receptors and hormone receptors EGFR expression as under but also the mineralocorticoid The for MR with cells in the that the used not to the CHO-MR which is and MR was not this we used the MR which a on of the Y. F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) for the signal as well as the with hMR, that were to These data support hypothesis that MR expression in cells is transfection of to and it completely that MR a than The studies and the data on human cells in primary this hypothesis of EGFR expression we the effect of aldosterone in cell cells M. S. H. Silbernagl S. J. Physiol. PubMed Scopus Google Scholar), from cells have been used to study effects of the expression of MR in these cells has not been with from cells using the MR which of Y. F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The from has a of that we a of the which has to the human Thus, cells express MR we the cells for with aldosterone and EGFR expression. shown in aldosterone EGFR expression. These data support for hypothesis of EGFR expression. In addition, the of expression of MR in or of the used MR spironolactone EGFR expression in CHO-MR cells as shown in of serum for the expression of EGFR the However, serum was for the of the EGFR expression was the of aldosterone under EGFR expression However, aldosterone was than This can by serum factors EGFR expression. The action of aldosterone on EGFR expression was and inhibited by spironolactone. These data show that EGFR expression can by the aldosterone the EGFR is downstream we EGF-induced ERK1/2 In cells, EGF-induced ERK1/2 phosphorylation to EGF in to cells the ERK1/2 phosphorylation was not to aldosterone in cells (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), we a increase in ERK1/2 phosphorylation in of the CHO-MR cell after of aldosterone the mechanisms underlying this effect are not increase in EGFR expression can not explain this because cells respond to aldosterone only in the of EGF (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Most the MR is for the This is under the that enhanced EGF-induced ERK1/2 phosphorylation is because of enhanced ERK1/2 expression, we the expression in and cells but not shown in of the CHO-MR to The to for ERK1/2 was similar in and cells EGF-induced ERK1/2 phosphorylation was with an of EGF-induced ERK1/2 phosphorylation was prevented by of the EGFR kinase using or by of which ERK1/2 using Thus, MR and aldosterone the expression of a EGFR with downstream signaling EGF responsiveness of cells also by MR transfection after transfection with MR, of EGF for ERK1/2 phosphorylation to of transfection was These data the of to cell by the effects are for or can also by hGR, cells were with Subsequently, cell were and for EGFR expression. shown in EGFR expression In addition, we the EGF responsiveness of the cells with respect to ERK1/2 of the to PMA, of to EGF These data show that the stimulation of EGFR expression is for MR with Thus, of EGFR expression to the of MR action most proteins that are by MR can also by support for the effects of MR and on EGFR expression is by the EGFR transfection with of of a the EGFR activity after with the transfection with an of not enhance EGFR activity These support the hypothesis of the EGFR as a not analysis of the interaction between MR and the EGFR of transfection of the the activity of the EGFR This was not the for transfection we also the of CHO-MR cells to other peptide hormones with respect to ERK1/2 shown in the CHO-MR cells respond with enhanced ERK1/2 phosphorylation to and EGF but not to or we transfection to a of peptide hormone signaling. this we the effects of other and on that of these hormones a effect in of the CHO-MR cell Thus, we that EGF the signaling of is transfection with does not a of cell signaling. suggest that the mineralocorticoid hormone aldosterone the mineralocorticoid receptor in the regulation of EGFR expression. Thus, EGFR to an aldosterone-induced data can to explain studies, which suggest a between aldosterone to and EGFR expression (19Florian J.A. Dorrance A. Webb R.C. Watts S.W. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001; 281: R878-R886Crossref PubMed Google Scholar, A.M. Osborn H.L. Grekin R. Webb R.C. Am. J. Physiol. 2001; 281: R944-R950PubMed Google Scholar, J. Endocrinol. PubMed Scopus Google Scholar). various signaling pathways are involved in the regulation of EGFR expression and studies are to the by it is not MR binds to the EGFR However, MR also to EGFR expression, for activation of AP1 (15Fiebeler A. Schmidt F. Muller D.N. Park J.K. Dechend R. Bieringer M. Shagdarsuren E. Breu V. Haller H. Luft F.C. Hypertension. 2001; 37: 787-793Crossref PubMed Google Scholar). The of EGFR expression can also signaling of other hormones that interact with the EGFR by a (17Krug A.W. Schuster C. Gassner B. Freudinger R. Mildenberger S. Troppmair J. Gekle M. J. Biol. Chem. 2002; 277: 45892-45897Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). of the EGFR is used by a of with pathophysiological similar to or G. J. Cell Biol. 1999; PubMed Scopus Google Scholar). Thus, aldosterone the expression of a (EGFR) involved in various signaling and influence the action of a of signaling This data can also to explain the interaction of aldosterone with peptide hormone and cytokine signaling P. Petrov V. J. Mol. Cell Cardiol. 2000; 32: 865-879Abstract Full Text PDF PubMed Scopus (223) Google Scholar). this is a hypothesis that to in that the interaction of with EGFR is of importance especially with respect to aldosterone as a of cardiovascular and renal dysfunction because EGFR aldosterone for fibrosis, fibrosis, or (2Epstein M. Am. J. Kidney Dis. 2001; 37: 677-688Abstract Full Text PDF PubMed Scopus (141) Google Scholar, 3Epstein M. J. R. Soc. Med. 2001; 94: 378-383Crossref PubMed Scopus (62) Google Scholar, 6Lijnen P. Petrov V. J. Mol. Cell Cardiol. 2000; 32: 865-879Abstract Full Text PDF PubMed Scopus (223) Google Scholar, 16Stockand J.D. Meszaros J.G. Am. J. Physiol. 2003; 284: H176-H184Crossref PubMed Scopus (159) Google Scholar). to pathophysiological of aldosterone-induced EGFR expression on the These the of reactive oxygen species and of collagen or the role of EGFR in aldosterone-induced tissue has to in A. Johnson from the of for the

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