Absence of Mrp2 leads to differences in severity and pattern of mercury nephrotoxicity in mice

Abstract

The multidrug‐resistance associated protein 2 (Mrp2) is located on the luminal membrane of proximal tubular epithelial cells and has been shown to mediate the export of numerous endobiotics and xenobiotics such as mercury. Although Mrp2 is present in all proximal tubular cells, there is axial heterogeneity in the magnitude of expression along the three segments of the proximal tubule. The purpose of the current study was to assess differences in renal injury and disposition of mercury between Mrp2−/− and FVB mice following a toxic dose of mercuric chloride (HgCl2). Mrp2−/− and FVB mice were injected intraperitoneally with doses of HgCl2 ranging from 18 – 30 μmol/kg. Mice were sacrificed after 24 h and organs were harvested. The renal burden of mercury was significantly greater in Mrp2−/− mice than in FVB mice. Significant differences in pattern and severity of mercury‐induced injury were observed between Mrp2−/− and FVB mice, with the most severe changes observed in Mrp2−/−mice. Histological analyses showed that degenerative change and necrosis occurred as low as 18.5 μmol/kg HgCl2 and the severity of these changes increased as the dose of HgCl2 increased. Our results suggest that the activity of Mrp2 is an important factor in the disposition and nephrotoxicity of HgCl2. This work was supported by NIH ES019991–01 (NIEHS) awarded to CC Bridges.