title: Endoplasmic reticulum stress eIF2α-ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney.
abstract: The heavy metal cadmium (Cd) is nephrotoxic. Recent studies show that autophagy plays an essential role in Cd-induced kidney injury. However, the mechanisms of Cd-induced kidney injury accompanied by autophagy are still obscure. In the present study, we first confirmed that Cd induced kidney damage and dysfunction, along with autophagy, both in vivo and in vitro. Then, we observed that cyclooxygenase-2 (COX-2) and the eIF2α-ATF4 pathway of endoplasmic reticulum (ER) stress were induced by Cd in both kidney tissues and cultured cells. Further studies showed that inhibition of COX-2 with celecoxib or RNA interference (RNAi) inhibited the Cd-induced autophagy in kidney cells. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and autophagy induced by Cd, which suggested that ER stress was required for Cd-induced kidney autophagy. Significantly, our results showed that Cd activated ATF4 and induced its translocation to the nucleus. Knockdown of ATF4 inhibited Cd-induced COX-2 overexpression. While COX-2 overexpression is involved in renal dysfunction, there is no prior report on the role of COX-2 in autophagy regulation. The results of the current study suggest a novel molecular mechanism that the ER stress eIF2α-ATF4 pathway-mediated COX-2 overexpression contributes to Cd-induced kidney autophagy and injury. The present study implies that COX-2 may be a potential target for therapy against Cd-induced nephrotoxicity.
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: B
authors.initials: B
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: S
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: R
authors.initials: R
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: C
authors.initials: C
authors.lastname: He
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Lin
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D008813:Mice, Inbred ICR; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D015852:Eukaryotic Initiation Factor-2; D002104:Cadmium; D051701:Activating Transcription Factor 4; D051546:Cyclooxygenase 2