title: Up-regulation of early growth response gene-1 via the CXCR3 receptor induces reactive oxygen species and inhibits Na+/K+-ATPase activity in an immortalized human proximal tubule cell line.
abstract: The CXCR3 chemokine receptor, a member of the CXCR family, has been linked to a pathological role in autoimmune disease, inflammatory disease, allograft rejection, and ischemia. In the kidney, expression of the CXCR3 receptor and its ligands is up-regulated in states of glomerulonephritis and in allograft rejection, but little is known about the expression and functional role the CXCR3 receptor might play. Here, we study the function of the CXCR3 chemokine receptor in an immortalized human proximal tubular cell line (IHKE-1). Stimulation of the CXCR3 receptor by its selective agonist monokine induced by IFN-gamma leads via a Ca(2+)-dependent mechanism to an up-regulation of early growth response gene (EGR)-1. Overexpression of EGR-1 induces down-regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase and stimulates the generation of reactive oxygen species (ROS) via the NADH/NADPH-oxidase system. EGR-1 overexpression or treatment with monokine induced by IFN-gamma resulted in a ROS-dependent inhibition of basolateral Na(+)/K(+)-ATPase activity, compromising sodium transport in these cells. Thus, activation of the CXCR3 receptor in proximal tubular cells might disturb natriuresis during inflammatory and ischemic kidney disease via EGR-1-mediated imbalance of ROS.
authors.affiliation: Department of Medicine, Division of Nephrology and General Medicine, University of Freiburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Bek
authors.forename: Hans C
authors.initials: HC
authors.lastname: Reinhardt
authors.forename: Karl-Georg
authors.initials: KG
authors.lastname: Fischer
authors.forename: Jochen R
authors.initials: JR
authors.lastname: Hirsch
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hupfer
authors.forename: Eileen
authors.initials: E
authors.lastname: Dayal
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
mesh_terms: D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002461:Cell Line, Transformed / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000276:immunology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014157:Transcription Factors; D007371:Interferon-gamma; D013482:Superoxide Dismutase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium