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1 Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX, USA
2 Science Park - Research Division, UTMDACC, Smithville, TX, USA
3 Eli Lilly and Company, Greenfield, IN, USA
4 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Science Center, Tucson, AZ, USA
* To whom correspondence should be addressed. E-mail: lau{at}pharmacy.arizona.edu.
11-Deoxy-16, 16-dimethyl prostaglandin E2 (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 TNF
. DDM-PGE2 mediated cytoprotection is
associated with the up-regulation of at least five proteins, including the major endoplasmic reticulum (ER) chaperone Grp78. To elucidate the role of Grp78 in oncotic
cell death, we utilized 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 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 2D gel coupled to MALDI-TOF, 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 shoc protein 27. The findings suggest that additional proteins may act in concert with Grp78 during DDM-PGE2 mediated cytoprotection against oncotic cell death.
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