title: A potential adjuvant chemotherapeutics, 18β-glycyrrhetinic acid, inhibits renal tubular epithelial cells apoptosis via enhancing BMP-7 epigenetically through targeting HDAC2.
abstract: Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by an effective adjuvant via epigenetic modification through targeting HDAC2. Molecular docking and SPR assay firstly reported that 18βGA, major metabolite of GA, could directly bind to HDAC2 and inhibit the activity of HDAC2. The effects and mechanisms of GA and 18βGA were assessed in CP-induced AKI in C57BL/6 mice, and in CP-treated HK-2 and mTEC cells lines. TUNEL and FCM results confirmed that GA and 18βGA could inhibit apoptosis of renal tubular epithelial cells induced by CP in vivo and in vitro. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by 18βGA in AKI models while siRNA BMP-7 could reduce the inhibitory effect of 18βGA on apoptosis. Results of current study indicated that 18βGA inhibited apoptosis of renal tubular epithelial cells via enhancing the level of BMP-7 epigenetically through targeting HDAC2, therefore protecting against CP-induced AKI. These available evidence, which led to an improved understanding of molecular recognition, suggested that 18βGA could serve as a potential clinical adjuvant in chemotherapy.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.|School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Taotao
authors.initials: T
authors.lastname: Ma
authors.affiliation: School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Meng
authors.affiliation: School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Ji
authors.affiliation: School of pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000009:adverse effects*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; C119129:18alpha-glycyrrhetinic acid; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D006034:Glycyrrhetinic Acid; D002945:Cisplatin