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  • Title: Stress protein activation by the cyclopentenone prostaglandin 15-deoxy-delta12,14-prostaglandin J2 in human mesangial cells.
    Author: Zhang X, Lu L, Dixon C, Wilmer W, Song H, Chen X, Rovin BH.
    Journal: Kidney Int; 2004 Mar; 65(3):798-810. PubMed ID: 14871400.
    Abstract:
    BACKGROUND: The cyclopentenone prostaglandin 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) affects mesangial proliferation, survival and production of proinflammatory proteins. During a survey of the mesangial cell proteome after treatment with 15dPGJ2, heat shock protein 70 (HSP70) was found to be the most conspicuously up-regulated protein, suggesting that stress proteins are key mediators or modulators of the effects of 15dPGJ2. Because cyclopentenone prostaglandins are highly reactive toward intracellular thiols, the role of intracellular thiol modification in the stress response to 15dPGJ2 was examined. METHODS: Human mesangial cells were treated with 15dPGJ2 and intracellular thiol status was monitored by the fluorescent thiol probe monobromobimane (MBB). Specific intracellular thiol pools were manipulated by treating the cells with buthionine sulfoximine (BSO) to deplete glutathione (GSH), or phenylarsine oxide (PAO) to modify protein vicinal dithiols. Transcription pathways were examined with reporter gene or adenoviral constructs. RESULTS: 15dPGJ2 decreased mesangial GSH and other intracellular thiols, but depletion of GSH specifically with BSO did not induce HSP70. Thiol-replenishing reagents, which can restore modified protein thiols, attenuated 15dPGJ2-induced HSP70 levels. Furthermore, PAO mimicked the effects of 15dPGJ2 on HSP70. 15dPGJ2 also activated the stress-responsive transcription factor Nrf2, which requires thiol modification of its cytoplasmic inhibitor protein for transcriptional activity, and induced the Nrf2-dependent stress protein heme oxygenase-1 (HO-1). CONCLUSION: 15dPGJ2 activates a stress response in human mesangial cells by covalent modification of protein thiols through its unique cyclopentenone ring structure. This stress response may be beneficial in preventing renal cell injury or death during kidney inflammation or ischemia.
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