Raj Kumar Yadav (전북대학교 의과대학) | 한빛사논문 > 한빛사

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Raj Kumar YadavRaj Kumar Yadav

전북대학교 의과대학

Autophagy, Accepted author version posted online: 25 Aug 2015 | DOI:10.1080/15548627.2015.1082021 TMBIM6 (transmembrane BAX inhibitor motif containing 6) Enhances Autophagy and Reduces Renal Dysfunction in a Cyclosporine A-induced nephrotoxicity model

Abstract

Raj Kumar Yadav^a#, Geum-Hwa Lee^a#, Hwa-Young Lee^a, Bo Lia, Han-Eul Jung^a, Harun-Or Rashid, Min Kyung Choi^a, Binod Kumar Yadav^b, Woo-Ho Kim^c, Kyung-Woon Kim^d, Byung-Hyun Park^e, Won Kim^f, Yong-Chul Lee^f, Hyung-Ryong Kim^g* & Han-Jung Chae^a*

^a Department of Pharmacology and Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Chonbuk 561-180, Republic of Korea

^b Department of Biochemistry, Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal

^c Department of Pathology, Seoul National University Medical School, Seoul, 110-799, Republic of Korea

^d Animal Biotechnology Division, National Institute of Animal Science, RDA, Wanju-gun, Chonbuk, 565-851, Republic of Korea

^e Departments of Biochemistry, Chonbuk National University Medical School, Jeonju, Chonbuk, 561-756, Republic of Korea

^f Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-180, Republic of Korea

^g Department of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Republic of Korea

^*Corresponding authors
^#These authors contributed equally to this work.

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.

Keywords : Autophagy, Bax inhibitor-1, cyclosporine A, ER stress, nephrotoxicity, ACTB/β-actin, actin, beta, PRKKA/AMPK, protein kinase, AMP-activated, alpha 1 catalytic subunit/AMP-activated protein kinase, Baf, bafilomycin A1, BAX, BCL2-associated X protein, Ca2+, calcium, CsA, cyclosporine, CTSB, cathepsin B, EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1, ER, endoplasmic reticulum, GFP, green fluorescent protein, GLB1/β-galactosidase, galactosidase, beta 1, GUSB/β-glucuronidase, glucuronidase, beta, H&E, hematoxylin and eosin, HK-2, human kidney 2, LAMP2, lysosomal-associated membrane protein 2, MAN/α-mannosidase, mannosidase, alpha, MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta, MTORC1, mechanistic target of rapamycin (serine/threonine kinase) complex 1, NC, negative control, PAS, periodic acid-schiff, PBS, phosphate-buffered saline, RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1, SQSTM1/p62, sequestosome 1, TFEB, transcription factor EB, TMBIM6/BI-1, transmembrane BAX inhibitor motif containing 6, V-ATPase, vacuolar-type H+-ATPase, WT, wild type

논문정보

형식Research article
게재일2015년 08월 (BRIC 등록일 2015-09-01)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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