Contribution of Heat Shock Protein 27 and Retinol Binding Protein to 11-Deoxy-16, 16-Dimethyl Prostaglandin E2 Mediated Cytoprotection

Persistent Link:
http://hdl.handle.net/10150/193884
Title:
Contribution of Heat Shock Protein 27 and Retinol Binding Protein to 11-Deoxy-16, 16-Dimethyl Prostaglandin E2 Mediated Cytoprotection
Author:
Lord-Garcia, Jean Lanette
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
11-Deoxy-16,16-dimethyl prostaglandin E2 (DDM-PGE2) protects renal proximal tubular epithelial cells (LLC-PK1) against oncotic cell death induced by 2,3,5-tris(glutathione-S-yl)hydroquinone (TGHQ). Cytoprotection is associated with the up-regulation of several proteins including actin, heat shock protein 27 (Hsp27) and retinol binding protein (RBP). This dissertation reveals the induction and phosphorylation of Hsp27 by TGHQ treatment and DDM-PGE2 pretreatment. Treatment with TGHQ results in a dose-dependent disruption of the actin cytoskeleton that correlates with a decrease in cell viability, increased generation of reactive oxygen species, and the induction of Hsp27 nuclear translocation and co-localization with actin. Moreover, DDM-PGE2 pretreatment, but not co-treatment, prevents both TGHQ generation of ROS and actin cytoskeletal damage. DDM-PGE2 results in the enhanced induction and phosphorylation of nuclear Hsp27 that likely contributes to the inhibition of early effects of TGHQ induced ROS generation on the actin cytoskeleton. In correlation, we identify site specific phosphorylation of Hsp27 (p-Hsp27) at human Ser82 that negatively regulates cell survival, and p-Hsp27 at Ser15 associated with cell survival. We provide evidence that the TP receptor dependent increase in RBP expression is based on the ability of DDM-PGE2 to recruit the retinoid signaling pathway through activation of the RAR/RXR nuclear receptor heterodimers. All-trans retinoic acid (AtRA) pretreatment recapitulates the protective effects of DDM-PGE2 through a mechanism independent of TP receptor activation and the cytoprotective effects of AtRA were also investigated using an in vivo model. Finally, the ability of DDM-PGE2 to increase the cells antioxidant response, important in its cytoprotection against ROS is described. Taken together, these studies contribute to the mechanism of protection and will give insight into the affects of novel therapeutics in the modulation of chemical induced nephrotoxicity.
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Lau, Serrine S.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleContribution of Heat Shock Protein 27 and Retinol Binding Protein to 11-Deoxy-16, 16-Dimethyl Prostaglandin E2 Mediated Cytoprotectionen_US
dc.creatorLord-Garcia, Jean Lanetteen_US
dc.contributor.authorLord-Garcia, Jean Lanetteen_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstract11-Deoxy-16,16-dimethyl prostaglandin E2 (DDM-PGE2) protects renal proximal tubular epithelial cells (LLC-PK1) against oncotic cell death induced by 2,3,5-tris(glutathione-S-yl)hydroquinone (TGHQ). Cytoprotection is associated with the up-regulation of several proteins including actin, heat shock protein 27 (Hsp27) and retinol binding protein (RBP). This dissertation reveals the induction and phosphorylation of Hsp27 by TGHQ treatment and DDM-PGE2 pretreatment. Treatment with TGHQ results in a dose-dependent disruption of the actin cytoskeleton that correlates with a decrease in cell viability, increased generation of reactive oxygen species, and the induction of Hsp27 nuclear translocation and co-localization with actin. Moreover, DDM-PGE2 pretreatment, but not co-treatment, prevents both TGHQ generation of ROS and actin cytoskeletal damage. DDM-PGE2 results in the enhanced induction and phosphorylation of nuclear Hsp27 that likely contributes to the inhibition of early effects of TGHQ induced ROS generation on the actin cytoskeleton. In correlation, we identify site specific phosphorylation of Hsp27 (p-Hsp27) at human Ser82 that negatively regulates cell survival, and p-Hsp27 at Ser15 associated with cell survival. We provide evidence that the TP receptor dependent increase in RBP expression is based on the ability of DDM-PGE2 to recruit the retinoid signaling pathway through activation of the RAR/RXR nuclear receptor heterodimers. All-trans retinoic acid (AtRA) pretreatment recapitulates the protective effects of DDM-PGE2 through a mechanism independent of TP receptor activation and the cytoprotective effects of AtRA were also investigated using an in vivo model. Finally, the ability of DDM-PGE2 to increase the cells antioxidant response, important in its cytoprotection against ROS is described. Taken together, these studies contribute to the mechanism of protection and will give insight into the affects of novel therapeutics in the modulation of chemical induced nephrotoxicity.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairLau, Serrine S.en_US
dc.contributor.committeememberLau, Serrine S.en_US
dc.contributor.committeememberVaillancourt, Richard R.en_US
dc.contributor.committeememberRegan, John W.en_US
dc.contributor.committeememberLantz, Clark R.en_US
dc.contributor.committeememberMonks, Terrence J.en_US
dc.identifier.proquest2732en_US
dc.identifier.oclc659749752en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.