Title: Selective activation in the MAPK pathway by Hg(II) in precision-cut rabbit renal cortical slices.

Authors: Turney, K D; Parrish, A R; Orozco, J; Gandolfi, A J

Published In Toxicol Appl Pharmacol, (1999 Nov 1)

Abstract: The kidneys are the primary organ for the accumulation and toxicity of inorganic mercury. In these studies the molecular response of precision-cut rabbit renal cortical slices to low levels of inorganic mercury was examined. Cortical slices (275 microm) were obtained from 1.0 kg NZW rabbits and exposed to mercuric chloride [Hg(II)] at concentrations of 0.01-10 microM for 2-8 h. Overt cytotoxicity, as assessed by intracellular K(+) levels, was not observed following exposure to these concentrations of Hg(II). However, an induction of heme-oxygenase-1 (Hsp32) was seen following a 2-h challenge to Hg(II). A dose-dependent induction of the DNA binding activity of the AP-1 transcription factor after 4 h of Hg(II) exposure correlated with a dose-dependent enhancement of c-jun gene expression following 2 h of Hg(II) exposure. Additionally, an increase in phosphorylated c-Jun NH(2)-terminal protein kinase (JNK) was observed following 2 h of Hg(II) exposure. These results suggest activation of the mitogen-activated protein (MAP) signal transduction pathway, specifically the c-Jun NH(2)-terminal protein kinase (JNK) pathway. No changes were observed, however, in the DNA binding activity of ATF2 and Elk-1, transcription factors involved in both the JNK and p38 pathways of MAP signal transduction, nor in the gene expression of c-myc. This selectivity of alterations in molecular signaling suggests an acute response in signal transduction, specifically activation of the JNK pathway in renal tissue following exposure to nanomolar concentrations of Hg(II).

PubMed ID: 10544060

MeSH Terms: Activating Transcription Factor 2; Animals; Blotting, Western; Cell Survival/drug effects; Cyclic AMP Response Element-Binding Protein/metabolism; DNA-Binding Proteins/metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Activation/drug effects; Gene Expression/drug effects; Genes, jun/genetics; Heme Oxygenase (Decyclizing)/biosynthesis; Heme Oxygenase-1; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases; Kidney Cortex/drug effects*; Kidney Cortex/enzymology; Male; Mercuric Chloride/toxicity*; Mitogen-Activated Protein Kinases/metabolism*; Potassium/metabolism; Proto-Oncogene Proteins/metabolism; Rabbits; Signal Transduction; Transcription Factor AP-1/metabolism; Transcription Factors/metabolism; ets-Domain Protein Elk-1