title: From the Cover: Ethylmercury-Induced Oxidative and Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death: Involvement of Autophagosome-Lysosome Fusion Arrest.
abstract: Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca2+levels in HK-2 cells. Cell death induced by EtHg exposure was caused by autophagy and necrosis. N-acetyl cysteine and 4-phenylbutyric acid attenuated EtHg-induced stress and ameliorated the autophagic response in HK-2 cells. Furthermore, EtHg blocked autophagosome fusion with lysosomes, which was demonstrated via treatment with wortmannin and chloroquine. Low doses of EtHg and rapamycin, which resulted in minimal cytotoxicity, increased the levels of the autophagic SNARE complex STX17 (syntaxin 17)-VAMP8-SNAP29 without altering mRNA levels, but high dose of EtHg was cytotoxic. Inhibition of autophagic flux by chloroquin increased autophagosome formation and necrotic cell death in HK-2 cells. Collectively, our results show that EtHg induces autophagy via oxidative and ER stress and blockade of autophagic flux. Autophagy might play a dual role in EtHg-induced renal toxicity, being both protective following treatment with low doses of EtHg and detrimental following treatment with high doses.
authors: *School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors: Ji-Yoon
authors: JY
authors: Choi
authors: College of Medicine, Korea University, Seoul, Korea.
authors: Nam-Hee
authors: NH
authors: Won
authors: College of Medicine, Chung-Ang University, Seoul, Korea.
authors: Jung-Duck
authors: JD
authors: Park
authors: Seoul Center, Korea Basic Science Institute, Seoul, Korea.
authors: Sinae
authors: S
authors: Jang
authors: Seoul Center, Korea Basic Science Institute, Seoul, Korea.
authors: Chi-Yong
authors: CY
authors: Eom
authors: *School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors: Yongseok
authors: Y
authors: Choi
authors: College of Pharmacy, Korea University, Sejong, Korea yipark@korea.ac.kr.
authors: Young In
authors: YI
authors: Park
authors: *School of Life Sciences and Biotechnology, Korea University, Seoul, Korea; msdong@korea.ac.kr.
authors: Mi-Sook
authors: MS
authors: Dong
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects*; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005035:Ethylmercury Compounds / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D005035:Ethylmercury Compounds; D017382:Reactive Oxygen Species; D002118:Calcium
keywords: ER stress; autophagy; blocking autophagic flux; ethylmercury; mitochondrial dysfunction