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

Although the kidney represents a target for the accumulation and toxicity o f arsenic, little is known about the molecular targets of arsenic in this o rgan. Therefore, these studies were designed to examine the molecular impac t of arsenite [As(III)] and arsenate [As(V)] at low (nanomolar) concentrati ons. Precision-cut rabbit renal cortical slices were challenged with As(III ) or As(V) for up to 8 h. Neither form of the metal induced overt cytotoxic ity as assessed by intracellular K+ levels over this time period at concent rations from 0.01-10 mu M. In addition, no alterations in the expression of Hsp 60, 70, or 90 were observed. However, induction of heme oxygenase-1 (H sp 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- and 4-h exposure; foll owing a 6-h exposure there was no difference. Although no alteration in the DNA binding activity of ATF-2 was induced by As(III) or As(V), both forms enhanced the DNA binding activity of Elk-1. Enhanced DNA binding activity o f AP-1 and Elk-1 correlated with increased gene expression of c-fos, but no t c-jun, at 2 h. c-mye gene expression was also induced by As(III) and As(V ), albeit at a later time point (6 h). These results suggest that acute ars enic challenge, by either As(III) or As(V), is associated with discrete alt erations in the activity of signaling pathways and gene expression in renal tissue.