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PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced non-apoptotic cell death
Zhang, FJ1; Xie, RY1,2,3; Munoz, FM1; Lau, SS1; Monks, TJ1
2014
Source PublicationTOXICOLOGICAL SCIENCES
ISSN2014
Volume140Issue:1Pages:118-134
Abstract

The generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions. DNA strand breaks caused by ROS lead to the activation of poly(ADP-ribose)polymerase-1 (PARP-1), the excessive activation of which can result in cell death. We have utilized a model in which 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a nephrotoxic and nephrocarcinogenic metabolite of hydroquinone, causes ROS-dependent cell death in human renal proximal tubule epithelial cells (HK-2), to further elucidate the role of PARP-1 in ROS-dependent cell death. TGHQ-induced ROS generation, DNA strand breaks, hyperactivation of PARP-1, rapid depletion of nicotinamide adenine dinucleotide (NAD), elevations in intracellular Ca2+ concentrations, and subsequent nonapoptotic cell death in both a PARP- and Ca2+-dependent manner. Thus, inhibition of PARP-1 with PJ34 completely blocked TGHQ-mediated accumulation of poly(ADP-ribose) polymers and NAD consumption, and delayed HK-2 cell death. In contrast, chelation of intracellular Ca2+ with BAPTA completely abrogated TGHQ-induced cell death. Ca2+ chelation also attenuated PARP-1 hyperactivation. Conversely, inhibition of PARP-1 modulated TGHQ-mediated changes in Ca2+ homeostasis. Interestingly, PARP-1 hyperactivation was not accompanied by the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus, a process usually associated with PARP-dependent cell death. Thus, pathways coupling PARP-1 hyperactivation to cell death are likely to be context-dependent, and therapeutic strategies designed to target PARP-1 need to recognize such variability. Our studies provide new insights into PARP-1-mediated nonapoptotic cell death, during which PARP-1 hyperactivation and elevations in intracellular Ca2+ are reciprocally coupled to amplify ROS-induced nonapoptotic cell death.

关键词

Keyword2,3,5-tris(Glutathion-s-yl)Hydroquinone Hk-2 Cells Reactive Oxygen Species Poly(Adp-ribose)Polymerase Apoptosis-inducing Factor-1 Intracellular Ca2++++
DOIhttp://dx.doi.org/10.1093/toxsci/kfu073
Indexed BySCI
Language英语
WOS Research AreaToxicology
WOS SubjectToxicology
WOS IDWOS:000339722100012
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Citation statistics
Cited Times [WOS]:20   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Hlth Sci Ctr, Tucson, AZ 85721 USA
2.Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
3.Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
Recommended Citation
GB/T 7714
Zhang, FJ,Xie, RY,Munoz, FM,et al. PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced non-apoptotic cell death[J]. TOXICOLOGICAL SCIENCES,2014,140(1):118-134.
APA Zhang, FJ,Xie, RY,Munoz, FM,Lau, SS,&Monks, TJ.(2014).PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced non-apoptotic cell death.TOXICOLOGICAL SCIENCES,140(1),118-134.
MLA Zhang, FJ,et al."PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS-induced non-apoptotic cell death".TOXICOLOGICAL SCIENCES 140.1(2014):118-134.
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