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Jia Z, Person MD, Dong J, Shen J, Hensley SC, Stevens JL, Monks TJ, Lau SS: Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells. Am J Physiol Renal Physiol. 2004 Dec;287(6):F1113-22. Epub 2004 Jun 29.
11-Deoxy-16,16-dimethyl PGE (2) (DDM-PGE (2)) protects renal proximal tubule epithelial cells (LLC-PK (1)) 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-PGE (2) to protect against other renal toxicants and report that DDM-PGE (2) only protects against oncotic cell death, induced by H (2) O (2), iodoacetamide, and TGHQ, but not against apoptotic cell death induced by cisplatin, mercuric chloride, or tumor necrosis factor-alpha. DDM-PGE (2)-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-PK (1) cells in which induction of grp78 expression was disrupted by stable expression of an antisense grp78 RNA (pkASgrp78). As anticipated, DDM-PGE (2) failed to induce Grp78 in pkASgrp78 cells, with a concomitant inability to provide cytoprotection. In contrast, DDM-PGE (2) induced Grp78 and afforded cytoprotection against H (2) O (2), iodoacetamide, and TGHQ in empty vector transfected cells (pkNEO). These data suggest that Grp78 plays an essential role in DDM-PGE (2)-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-PGE (2) 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-PGE (2)-mediated cytoprotection against oncotic cell death. |
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