title: EGF and its related growth factors mediate sodium transport in mpkCCDc14 cells via ErbB2 (neu/HER-2) receptor.
abstract: Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate-limiting step for Na(+) absorption. Epidermal growth factor (EGF) is involved in the regulation of Na(+) transport and ENaC activity. However it is still controversial exactly how EGF regulates ENaC and Na(+) absorption. The aim of the present study was to characterize the EGF regulation of Na(+) transport in cultured mouse renal collecting duct principal mpkCCD(c14) cells, a highly differentiated cell line which retains many characteristics of the cortical collecting duct (CCD). EGF dose dependently regulates basal transepithelial Na(+) transport in two phases: an acute phase (<4 h) and a chronic phase (>8 h). Similar effects were observed with TGF-alpha, HB-EGF, and amphiregulin which also belong to the EGF-related peptide growth factor family. Inhibition of MEK1/2 by PD98059 or U0126 increased acute effects and disrupted chronic effects of EGF on Na(+) reabsorption. Inhibition of PI3-kinase with LY294002 abolished acute effect of EGF. As assessed by Western blotting, ErbB2 is the most predominant member of the ErbB family detected in mpkCCD(c14) cells. Immunohistochemistry analysis revealed localization of ErbB2 in the CCD in Sprague-Dawley rat kidneys. Both acute and long-term effects of EGF were abolished when cells were treated with tyrphostin AG-825 and ErbB2 inhibitor II, chemically dissimilar selective inhibitors of the ErbB2 receptor. Thus, we conclude that EGF and its related growth factors are important for maintaining transepithelial Na(+) transport and that EGF biphasically modulates sodium transport in mpkCCD(c14) cells via the ErbB2 receptor.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Levchenko
authors.forename: Nadezhda N
authors.initials: NN
authors.lastname: Zheleznova
authors.forename: Tengis S
authors.initials: TS
authors.lastname: Pavlov
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Wilson
authors.forename: Alexander
authors.initials: A
authors.lastname: Staruschenko
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D066258:Amphiregulin; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D017136:Ion Transport; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000584:Amiloride; D066258:Amphiregulin; D052160:Benzothiazoles; D002070:Butadienes; D002867:Chromones; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D053503:Epithelial Sodium Channels; D005419:Flavonoids; D006023:Glycoproteins; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D012964:Sodium; D026941:Sodium Channel Blockers; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C587849:Areg protein, mouse; C587850:Areg protein, rat; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; C113580:U 0126; C098214:tyrphostin AG825; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C524056:Erbb2 protein, mouse; C483804:Erbb2 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one