Enhanced transcription factor DNA binding and gene expression induced by arsenite or arsenate in renal slices

Although the kidney represents a target for the accumulation and toxicityof arsenic, little is known about the molecular targets of arsenic in thisorgan. Therefore, these studies were designed to examine the molecularimpact of arsenite [As(III)] and arsenate [As(V)] at low (nanomolar)concentrations. Precision-cut rabbit renal cortical slices were challengedwith As(III) or As(V) for up to 8 h. Neither form of the metal inducedovert cytotoxicity as assessed by intracellular K+ levels over this timeperiod at concentrations from 0.01-10 microM. In addition, no alterationsin the expression of Hsp 60, 70, or 90 were observed. However, induction ofheme oxygenase-1 (Hsp 32) was seen following a 4-h challenge with As(III),but not with As(V). As(III) and As(V) induced DNA binding of AP-1 at 2- and4-h exposure; following a 6-h exposure there was no difference. Although noalteration in the DNA binding activity of ATF-2 was induced by As(III) orAs(V), both forms enhanced the DNA binding activity of Elk-1. Enhanced DNAbinding activity of AP-1 and Elk-1 correlated with increased geneexpression of c-fos, but not c-jun, at 2 h. c-myc gene expression was alsoinduced by As(III) and As(V), albeit at a later time point (6 h). Theseresults suggest that acute arsenic challenge, by either As(III) or As(V),is associated with discrete alterations in the activity of signalingpathways and gene expression in renal tissue.