title: Cycloartenyl Ferulate Inhibits Paraquat-Induced Apoptosis in HK-2 Cells With the Involvement of ABCC1.
abstract: Nephrotoxicity induced by chemicals such as paraquat (PQ) is a common clinical phenomenon; therefore, searching for drugs with renal protective effect is of a great practical significance. Our previous investigation found that cycloartenyl ferulate (CF) can antagonize the cytotoxic effect of PQ, and recent studies also revealed a variety of bioactivities of CF. However, specific molecular mechanisms underlying the protective effect of CF have not been explored yet. HPLC detection of PQ content indicated that CF reduced PQ accumulation in HK-2 cells and thereby improved cell survival. Western blot results showed that both PQ and CF did not affect the expression of ABCB1; however, while PQ suppressed the expression of ABCC1, CF upregulated ABCC1 expression and thereby reversed the inhibitory effect of PQ on ABCC1 expression. Meanwhile, HK-2 cells did not express ABCG2. When the expression of ABCC1 was knocked down with siRNA, the inhibitory effect of CF on intracellular PQ accumulation was blocked. Further flow cytometric analysis showed that while PQ significantly induced the appearance of sub-G1 apoptotic peak in cells, CF evidently inhibited apoptosis. TUNEL-DAPI double-staining also detected that PQ significantly induced the occurrence of DNA fragmentation in cells, whereas CF effectively inhibited the effect of PQ. Further results showed that ABCC1 siRNA effectively abolished the protective effect of CF on PQ-induced apoptosis. Taken together, these data demonstrated that in HK-2 cells, CF could antagonize PQ-induced toxicity with the involvement of regulatiion of ABCC1 protein expression, which provides a new strategy for treatments of nephrotoxicity.
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Guang-Liang
authors.initials: GL
authors.lastname: Hong
authors.affiliation: School of Environmental Science and Public Health, Wenzhou Medical University, 1210 University Town, Wenzhou, 325035, Zhejiang, China.
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Liu
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Guang-Ju
authors.initials: GJ
authors.lastname: Zhao
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Tan
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Meng-Fang
authors.initials: MF
authors.lastname: Li
authors.affiliation: School of Pharmacy, Wenzhou Medical University, 1210 University Town, Wenzhou, 325035, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Qiao-Meng
authors.initials: QM
authors.lastname: Qiu
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Lu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003373:Coumaric Acids / Q000494:pharmacology*; D003603:Cytotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D053938:DNA Fragmentation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D010269:Paraquat / Q000037:antagonists & inhibitors* / Q000633:toxicity; D020011:Protective Agents / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003373:Coumaric Acids; D003603:Cytotoxins; D009363:Neoplasm Proteins; D020011:Protective Agents; D034741:RNA, Small Interfering; C540967:cycloartenyl ferulate; D010269:Paraquat
keywords: ABCC1; APOPTOSIS; CYCLOARTENYL FERULATE; NEPHROTOXICITY; PARAQUAT