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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 Line¹

Martin J. Bek^*, Hans C. Reinhardt^*, Karl-Georg Fischer^*, Jochen R. Hirsch, Charlotte Hupfer^*, Eileen Dayal^* and Hermann Pavenstädt^2,*

^* Department of Medicine, Division of Nephrology and General Medicine, University of Freiburg, Freiburg, Germany; and Division of Experimental Nephrology, Medical Clinic and Polyclinic, University Clinic of Muenster, Muenster, Germany

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- leads via a Ca²⁺-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- 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.

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