title: Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation.
abstract: Neurological disease comprises a series of disorders featuring brain dysfunction and neuronal cell death. Among the factors contributing to neuronal death, excitotoxicity induced by excitatory amino acids, such as glutamate, plays a critical role. However, the mechanisms about how the excitatory amino acids induce neuronal death remain elucidated. In this study, we investigated the role of HIF-1α (hypoxia inducible factor-1α) and RTP801 in cell apoptosis induced by quinolinic acid (QUIN), a glutamatergic agonist, in PC12 cells. We found that QUIN at 5 μM increased the expression of HIF-1α significantly with a peak at 24 h. After the treatment with QUIN (5-20 μM) for 24 h, the cells exhibited decreased viability and cell apoptosis with a concomitant increased expression of apoptosis related proteins. QUIN treatment also induced the generation of intracellular reactive oxygen species and RTP801 up-regulation in a HIF-1α-dependent manner that were inhibited by 2-methoxyestradiol, a HIF-1α inhibitor. Importantly, HIF-1 or RTP801 invalidation by siRNA rescued the cell apoptosis induced by QUIN or cobalt chloride, a chemical inducer of HIF-1. Taken together, these findings support the concept that neurotoxicity induced by QUIN is associated with HIF-1-dependent RTP801 activation and provide insight into the potential of RTP801 inhibitor in treatment of neurological disorders.
authors.affiliation: Department of Pharmacology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China. huangxj@ujs.edu.cn.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Kaiyong
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects*; D003035:Cobalt / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016716:PC12 Cells; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: C000632146:Ddit4 protein, rat; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; D003035:Cobalt; C018021:cobaltous chloride; D017378:Quinolinic Acid
keywords: Cell apoptosis; Hypoxia inducible factor-1; Quinolinic acid; RTP801