Prostaglandins (PGs) are potent signaling molecules derived from arachidonic acid by the action of cyclooxygenase. PGs are synthesized by a broad spectrum of mammalian cells under both physiologic and pathologic conditions. The actions of prostanoids are diverse and they impact both cellular and systemic events based on pharmacologic concentration and/or the presence of distinct PG receptor subtypes. In addition, certain PGs have been shown to protect target cells against chemical-induced injury and this property has been termed cytoprotection. However, the mechanisms of PG-mediated cytoprotection remain unclear. In a model of chemical induced toxicity, the applicant has shown that 2,3,5-(trisgluathion-S-yl) hydroquinone [2,3,5-trisGSyl)HQ] is a potent and selective nephrotoxicant. Treatment of a renal proximal tubule epithelial cell line (LLC-PK1) with [2,3,5-trisGSyl)HQ] resulted in the rapid synthesis of PGE-2 and preliminary studies were conducted to delineate the role of PGE-2 in the nephrotoxic actions of [2,3,5-trisGSyl)HQ]. PGE-2 exhibits cytoprotective properties in the kidney, and in vitro studies suggest this event occurs at the cellular level. The cellular effects of PGE are receptor mediated and four PGE receptors (EP) have been identified and termed EP 1, EP2, EP3, and EP4. Preliminary studies using structurally distinct PGs demonstrated cytoprotection upon pretreatment of LLC-PK cells with PGE-2 and 11-deoxy-16,16-dimethyl PGE2 (DDM-PGE-2), but not with 17-phenyltrinor PGE2 (PT-PGE2; EPI agonist), 11-deoxy PGEI (EP2 agonist), sulprostone (EP3/EP1 agonist), PGEl, PGA2 or PGJ2. These studies suggest that PGE2 plays a cytoprotective role in renal proximal tubule epithelial cells and the observed structural specificity/requirements suggest this event is receptor-mediated. The two central hypotheses are (1) endogenous production of PGE2 within- the kidney is a beneficial stress response to chemical insult and 2) PGE2 derivatives exhibiting cytoprotective activity are an important intervention in renal dysfunction. Aithough several mechanisms have been proposed to explain the cytoprotective effects of PG's against chemical induced tissue injury, including PG-mediated alterations in blood flow, changes in metabolism of the toxicants or in membrane stability, and increases in the efficiency of tissue regeneration, there is, as yet, no consensus on the validity of any of these hypotheses. Of even greater significance is the fact that none of the currently proposed hypotheses directly address the molecular and cellular mechanisms of PG-mediated cytoprotection. Experiments detailed in the Preliminary Data and Experimental sections of this grant application directly address this deficiency in our knowledge.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056321-04
Application #
6386734
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Okita, Richard T
Project Start
1998-04-01
Project End
2003-08-31
Budget Start
2001-04-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$221,439
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Jia, Zhe; Person, Maria D; Dong, Jing et al. (2004) Grp78 is essential for 11-deoxy-16,16-dimethyl PGE2-mediated cytoprotection in renal epithelial cells. Am J Physiol Renal Physiol 287:F1113-22
Towndrow, Kelly M; Jia, Zhe; Lo, Herng-Hsiang et al. (2003) 11-Deoxy,16,16-dimethyl prostaglandin E2 induces specific proteins in association with its ability to protect against oxidative stress. Chem Res Toxicol 16:312-9
Person, Maria D; Lo, Herng-Hsiang; Towndrow, Kelly M et al. (2003) Comparative identification of prostanoid inducible proteins by LC-ESI-MS/MS and MALDI-TOF mass spectrometry. Chem Res Toxicol 16:757-67
Towndrow, K M; Mertens, J J; Jeong, J K et al. (2000) Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells. Chem Res Toxicol 13:111-7
Weber, T J; Monks, T J; Lau, S S (2000) DDM-PGE(2)-mediated cytoprotection in renal epithelial cells by a thromboxane A(2) receptor coupled to NF-kappaB. Am J Physiol Renal Physiol 278:F270-8