TY - JOUR
T1 - Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells
AU - Jia, Zhe
AU - Person, Maria D.
AU - Dong, Jing
AU - Shen, Jianjm
AU - Hensley, Sean C.
AU - Stevens, James L.
AU - Monks, Terrence J.
AU - Lau, Serrine S.
PY - 2004/12
Y1 - 2004/12
N2 - 11-Deoxy-16,16-dimethyl PGE2 (DDM-PGE2) protects renal proximal tubule epithelial cells (LLC-PK1) against the toxicity induced by 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a potent nephrotoxic and nephrocarcinogenic metabolite of hydroquinone. We have now determined the ability of DDM-PGE2 to protect against other renal toxicants and report that DDM-PGE2 only protects against oncotic cell death, induced by H2O2, iodoacetamide, and TGHQ, but not against apoptotic cell death induced by cisplatin, mercuric chloride, or tumor necrosis factor-α. DDM-PGE2-mediated cytoprotection is associated with the upregulation of at least five proteins, including the major endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (Grp78). To elucidate the role of Grp78 in oncotic cell death, we used LLC-PK1 cells in which induction of grp78 expression was disrupted by stable expression of an antisense grp78 RNA (pkASgrp78). As anticipated, DDM-PGE2 failed to induce Grp78 in pkASgrp78 cells, with a concomitant inability to provide cytoprotection. In contrast, DDM-PGE2 induced Grp78 and afforded cytoprotection against H2O2, iodoacetamide, and TGHQ in empty vector transfected cells (pkNEO). These data suggest that Grp78 plays an essential role in DDM-PGE2-mediated cytoprotection. Moreover, TGHQ-induced p38 MAPK activation is disrupted under conditions of a compromised ER stress response in pkASgrp78 cells, which likely contributes to the loss of cytoprotection. Finally, using two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, we found that DDM-PGE2 induced several proteins in pkNEO cells, but not in pkASgrp78 cells, including retinol-binding protein, myosin light chain, and heat shock protein 27. The findings suggest that additional proteins may act in concert with Grp78 during DDM-PGE2-mediated cytoprotection against oncotic cell death.
AB - 11-Deoxy-16,16-dimethyl PGE2 (DDM-PGE2) protects renal proximal tubule epithelial cells (LLC-PK1) against the toxicity induced by 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a potent nephrotoxic and nephrocarcinogenic metabolite of hydroquinone. We have now determined the ability of DDM-PGE2 to protect against other renal toxicants and report that DDM-PGE2 only protects against oncotic cell death, induced by H2O2, iodoacetamide, and TGHQ, but not against apoptotic cell death induced by cisplatin, mercuric chloride, or tumor necrosis factor-α. DDM-PGE2-mediated cytoprotection is associated with the upregulation of at least five proteins, including the major endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (Grp78). To elucidate the role of Grp78 in oncotic cell death, we used LLC-PK1 cells in which induction of grp78 expression was disrupted by stable expression of an antisense grp78 RNA (pkASgrp78). As anticipated, DDM-PGE2 failed to induce Grp78 in pkASgrp78 cells, with a concomitant inability to provide cytoprotection. In contrast, DDM-PGE2 induced Grp78 and afforded cytoprotection against H2O2, iodoacetamide, and TGHQ in empty vector transfected cells (pkNEO). These data suggest that Grp78 plays an essential role in DDM-PGE2-mediated cytoprotection. Moreover, TGHQ-induced p38 MAPK activation is disrupted under conditions of a compromised ER stress response in pkASgrp78 cells, which likely contributes to the loss of cytoprotection. Finally, using two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, we found that DDM-PGE2 induced several proteins in pkNEO cells, but not in pkASgrp78 cells, including retinol-binding protein, myosin light chain, and heat shock protein 27. The findings suggest that additional proteins may act in concert with Grp78 during DDM-PGE2-mediated cytoprotection against oncotic cell death.
KW - Endoplasmic reticulum stress
KW - Heat shock protein 27
KW - Proteomics
KW - Quinone-thioether
KW - Thromboxane receptor
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U2 - 10.1152/ajprenal.00138.2004
DO - 10.1152/ajprenal.00138.2004
M3 - Review article
C2 - 15226156
AN - SCOPUS:6344252131
SN - 1931-857X
VL - 287
SP - F1113-F1122
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6 56-6
ER -