Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells

Zhe Jia, Maria D. Person, Jing Dong, Jianjm Shen, Sean C. Hensley, James L. Stevens, Terrence Monks, Serrine Lau

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume287
Issue number6 56-6
DOIs
StatePublished - Dec 2004

Fingerprint

Cytoprotection
Epithelial Cells
Kidney
Cell Death
Iodoacetamide
LLC-PK1 Cells
HSP27 Heat-Shock Proteins
11-deoxy,16,16-dimethyl prostaglandin E(2)
glucose-regulated proteins
Antisense RNA
Retinol-Binding Proteins
Mercuric Chloride
Proximal Kidney Tubule
Myosin Light Chains
Proteins
Endoplasmic Reticulum Stress
Electrophoresis, Gel, Two-Dimensional
p38 Mitogen-Activated Protein Kinases
Endoplasmic Reticulum
Cisplatin

Keywords

  • Endoplasmic reticulum stress
  • Heat shock protein 27
  • Proteomics
  • Quinone-thioether
  • Thromboxane receptor

ASJC Scopus subject areas

  • Physiology

Cite this

Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells. / Jia, Zhe; Person, Maria D.; Dong, Jing; Shen, Jianjm; Hensley, Sean C.; Stevens, James L.; Monks, Terrence; Lau, Serrine.

In: American Journal of Physiology - Renal Physiology, Vol. 287, No. 6 56-6, 12.2004.

Research output: Contribution to journalArticle

Jia, Zhe ; Person, Maria D. ; Dong, Jing ; Shen, Jianjm ; Hensley, Sean C. ; Stevens, James L. ; Monks, Terrence ; Lau, Serrine. / Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells. In: American Journal of Physiology - Renal Physiology. 2004 ; Vol. 287, No. 6 56-6.
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abstract = "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.",
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AU - Person, Maria D.

AU - Dong, Jing

AU - Shen, Jianjm

AU - Hensley, Sean C.

AU - Stevens, James L.

AU - Monks, Terrence

AU - Lau, Serrine

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KW - Proteomics

KW - Quinone-thioether

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