title: TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model.
abstract: Cyclosporine A (CsA) is widely used as an immunosuppressor in transplantation. Previous studies reported that CsA induces autophagy and that chronic treatment with CsA results in accumulation of autophagosomes and reduced autophagic clearance. Autophagy is a prosurvival process that promotes recovery from acute kidney injury by degrading misfolded proteins produced in the kidney. In the present study, we used TMBIM6-expressing HK-2, human kidney tubular cells (TMBIM6 cells) and Tmbim6 knockout (tmbim6(-/-)) mice. When exposed to CsA, the TMBIM6 cells maintained autophagy activity by preventing autophagosome accumulation. With regard to signaling, PRKKA/AMPK phosphorylation and mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) expression and its downstream target TFEB (transcription factor EB), a lysosome biogenesis factor, were regulated in the TMBIM6 cells. Lysosomal activity was highly increased or stably maintained in the presence of TMBIM6. In addition, treatment of tmbim6(-/-) mice with CsA resulted in increased autophagosome formation and decreased lysosome formation and activity. We also found that tmbim6(-/-) mice were susceptible to CsA-induced kidney injury. Taken together, these results indicate that TMBIM6 protects against CsA-induced nephrotoxicity both in vitro and in vivo by inducing autophagy and activating lysosomes.
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Raj Kumar
authors: RK
authors: Yadav
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Geum-Hwa
authors: GH
authors: Lee
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Hwa-Young
authors: HY
authors: Lee
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Bo
authors: B
authors: Li
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Han-Eul
authors: HE
authors: Jung
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Harun-Or
authors: HO
authors: Rashid
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Min Kyung
authors: MK
authors: Choi
authors: b Department of Biochemistry, Maharajgunj Medical Campus; Institute of Medicine; Tribhuvan University ; Kathmandu , Nepal.
authors: Binod Kumar
authors: BK
authors: Yadav
authors: c Department of Pathology, Seoul National University Medical School ; Seoul , Korea.
authors: Woo-Ho
authors: WH
authors: Kim
authors: d Animal Biotechnology Division; National Institute of Animal Science ; RDA, Wanju-gun; Chonbuk , Korea.
authors: Kyung-Woon
authors: KW
authors: Kim
authors: e Department of Biochemistry, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Byung-Hyun
authors: BH
authors: Park
authors: f Department of Internal Medicine, Chonbuk National University Medical School ; Jeonju , Jeonbuk , Korea.
authors: Won
authors: W
authors: Kim
authors: f Department of Internal Medicine, Chonbuk National University Medical School ; Jeonju , Jeonbuk , Korea.
authors: Yong-Chul
authors: YC
authors: Lee
authors: g Department of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University ; Iksan , Chonbuk , Korea.
authors: Hyung-Ryong
authors: HR
authors: Kim
authors: a Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School ; Jeonju , Chonbuk , Korea.
authors: Han-Jung
authors: HJ
authors: Chae
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D008869:Microtubule-Associated Proteins; D016572:Cyclosporine; D020123:Sirolimus
keywords: Bax inhibitor-1; ER stress; autophagy; cyclosporine A; nephrotoxicity