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We have now determined the ability of DDM-PGE<jats:sub>2<\/jats:sub>to protect against other renal toxicants and report that DDM-PGE<jats:sub>2<\/jats:sub>only protects against oncotic cell death, induced by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>, iodoacetamide, and TGHQ, but not against apoptotic cell death induced by cisplatin, mercuric chloride, or tumor necrosis factor-\u03b1. DDM-PGE<jats:sub>2<\/jats:sub>-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<jats:sub>1<\/jats:sub>cells in which induction of grp78 expression was disrupted by stable expression of an antisense grp78 RNA (pkASgrp78). As anticipated, DDM-PGE<jats:sub>2<\/jats:sub>failed to induce Grp78 in pkASgrp78 cells, with a concomitant inability to provide cytoprotection. In contrast, DDM-PGE<jats:sub>2<\/jats:sub>induced Grp78 and afforded cytoprotection against H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>, iodoacetamide, and TGHQ in empty vector transfected cells (pkNEO). These data suggest that Grp78 plays an essential role in DDM-PGE<jats:sub>2<\/jats:sub>-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<jats:sub>2<\/jats:sub>induced several proteins in pkNEO cells, but not in pkASgrp78 cells, including retinol-binding protein, myosin light chain, and heat shock protein 27. 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