title: Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation.
abstract: Cisplatin is a chemotherapeutic drug but induces acute kidney injury (AKI). Cisplatin-induced AKI depends on several signaling pathways leading to apoptosis in tubular epithelial cells. Glutamine is a substrate for the synthesis of glutathione, the most abundant intracellular thiol and antioxidant, and plays an important role in protecting cells from apoptosis induced by different stimuli. In the present study, we investigated the protective effect of glutamine on cisplatin-induced AKI. Rats were divided into control, glutamine, cisplatin, and cisplatin plus glutamine groups. Glutamine ameliorated renal dysfunction, tissue injury, and cisplatin-induced apoptosis. Cisplatin increased cell death, caspase-3 cleavage, activation of MAPKs and p53, oxidative stress, and mRNA expression of TNF-α and TNFR1 in HK-2 cells. Glutamine treatment reduced cisplatin-induced these changes in HK-2 cells. Notably, glutamine reduced the cisplatin-induced expression of organic cation transporter 2 (OCT2) and cisplatin accumulation. Our results suggest that the protective effect of glutamine on cisplatin is specific for proximal tubular cells and the initial effects may be related to attenuation of cisplatin uptake. Thus, glutamine administration might represent a new strategy for the treatment of cisplatin-induced AKI.
authors.affiliation: Division of Nephrology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea; Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Jeong
authors.affiliation: Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Myeong Hee
authors.initials: MH
authors.lastname: Jung
authors.affiliation: Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jung Ill
authors.initials: JI
authors.lastname: Yang
authors.affiliation: Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea; Division of Hematology-Oncology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gyeong-Won
authors.initials: GW
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Division of Nephrology, Department of Internal Medicine School of Medicine, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea. Electronic address: shchang@gnu.ac.kr.
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Chang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects / Q000378:metabolism*; D005973:Glutamine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D000075102:Organic Cation Transporter 2; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D047888:Receptors, Tumor Necrosis Factor, Type I; C491013:SLC22A2 protein, human; D014409:Tumor Necrosis Factor-alpha; D005973:Glutamine; D053148:Caspase 3; D005978:Glutathione; D002945:Cisplatin
keywords: Acute kidney injury; Cisplatin; Cisplatin uptake; Glutamine; Nephrotoxicity