TY - JOUR
T1 - Induction of ERK1/2 and histone H3 phosphorylation within the outer stripe of the outer medulla of the Eker rat by 2,3,5- Tris-(Glutathion-S-yl) hydroquinone
AU - Dong, Jing
AU - Everitt, Jeffrey I.
AU - Lau, Serrine S.
AU - Monks, Terrence J.
N1 - Funding Information:
The authors would like to acknowledge the Center for Research on Environmental Diseases, Histology Core Facility, MD Anderson Cancer Research Center, Science Park, Smithville, Texas for the preparation of the paraffin slides and assistance with immunohistological techniques. This work was supported in part by NIEHS Center Grants P30 ES-07784 and P30 ES-06694, DK59491 to TJM, and GM39338 to SSL. Portions of this work were presented in abstract form at the 2002 Annual Meeting of the Society of Toxicology (Toxicol. Sci. 72(Suppl.), 64).
PY - 2004/8
Y1 - 2004/8
N2 - 2,3,5-tris-(glutathion-S-yl)-h ydroquinone (TGHQ), a metabolite of hydroquinone (HQ), generates reactive oxygen species (ROS) in cultured renal epithelial cells and binds to tissue macromolecules within the rat kidney. The potential mechanisms by which TGHQ induces nephrotoxicity and nephrocarcinogenesis have been examined in cell culture models, but less is known concerning the molecular mechanisms of TGHQ-induced nephrotoxicity in vivo. In LLC-PK1 cells, TGHQ induces phosphorylation of both mitogen-activated protein kinase and histone H3, which likely promotes inappropriate chromatin condensation and mitotic catastrophe. Using the Eker (Tsc-2 mutant) rat as a model, we show by immunohistochemistry that TGHQ (7.5 μmol/kg) selectively induces ERK1/2 phosphorylation within the outer stripe of the outer medulla (OSOM) of the kidney. ERK1/2 phosphorylation is time-dependant, occurring as early as 1 h following treatment, and reaching maximal levels by 4 h. Subsequently, ERK1/2 phosphorylation returns to baseline levels by 24 h post treatment. ERK1/2 phosphorylation was confirmed by western blot analysis of OSOM tissue. Increases in histone H3 phosphorylation occurred subsequent to ERK1/2 phosphorylation (8 h), and reached a peak by 24 h, coincident with histological evidence of tissue necrosis. In contrast to studies in cell culture, neither JNK/SAPK nor p38 MAPK phosphorylation were significantly altered after TGHQ administration in vivo, as evidenced by western blot and immunohistochemical analyses. These data indicate that activation of the ERK1/2 pathway precedes overt cytotoxicity and that the signaling pathways activated by TGHQ in vivo and in vitro differ.
AB - 2,3,5-tris-(glutathion-S-yl)-h ydroquinone (TGHQ), a metabolite of hydroquinone (HQ), generates reactive oxygen species (ROS) in cultured renal epithelial cells and binds to tissue macromolecules within the rat kidney. The potential mechanisms by which TGHQ induces nephrotoxicity and nephrocarcinogenesis have been examined in cell culture models, but less is known concerning the molecular mechanisms of TGHQ-induced nephrotoxicity in vivo. In LLC-PK1 cells, TGHQ induces phosphorylation of both mitogen-activated protein kinase and histone H3, which likely promotes inappropriate chromatin condensation and mitotic catastrophe. Using the Eker (Tsc-2 mutant) rat as a model, we show by immunohistochemistry that TGHQ (7.5 μmol/kg) selectively induces ERK1/2 phosphorylation within the outer stripe of the outer medulla (OSOM) of the kidney. ERK1/2 phosphorylation is time-dependant, occurring as early as 1 h following treatment, and reaching maximal levels by 4 h. Subsequently, ERK1/2 phosphorylation returns to baseline levels by 24 h post treatment. ERK1/2 phosphorylation was confirmed by western blot analysis of OSOM tissue. Increases in histone H3 phosphorylation occurred subsequent to ERK1/2 phosphorylation (8 h), and reached a peak by 24 h, coincident with histological evidence of tissue necrosis. In contrast to studies in cell culture, neither JNK/SAPK nor p38 MAPK phosphorylation were significantly altered after TGHQ administration in vivo, as evidenced by western blot and immunohistochemical analyses. These data indicate that activation of the ERK1/2 pathway precedes overt cytotoxicity and that the signaling pathways activated by TGHQ in vivo and in vitro differ.
KW - Eker rats
KW - Histone H3
KW - MAPK
KW - ROS
KW - TGHQ
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U2 - 10.1093/toxsci/kfh160
DO - 10.1093/toxsci/kfh160
M3 - Article
C2 - 15129024
AN - SCOPUS:4344661173
SN - 1096-6080
VL - 80
SP - 350
EP - 357
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -