title: Renoprotective effect of long acting thioredoxin by modulating oxidative stress and macrophage migration inhibitory factor against rhabdomyolysis-associated acute kidney injury.
abstract: Rhabdomyolysis-associated acute kidney injury (AKI) is a serious life-threatening condition. As such, more effective strategies are needed for its prevention. Thioredoxin-1 (Trx), a redox-active and macrophage migration inhibitory factor (MIF) modulating protein, has a short retention time in the blood. We examined the renoprotective effect of long acting Trx that was genetically fused with human serum albumin (HSA-Trx) against glycerol-induced AKI. An intravenous HSA-Trx pre-treatment attenuated the glycerol-induced decline in renal function, compared to a PBS, HSA or Trx alone. HSA-Trx caused a reduction in the tubular injuries and in the number of apoptosis-positive tubular cells. Renal superoxide, 8-hydroxy deoxyguanosine, nitrotyrosine and the plasma Cys34-cysteinylated albumin were clearly suppressed by the HSA-Trx treatment. Prior to decreasing TNF-α and IL-6, HSA-Trx suppressed an increase of plasma MIF level. In LLC-PK1 cells, HSA-Trx decreased the level of reactive oxygen species and lactate dehydrogenase release induced by myoglobin. HSA-Trx treatment resulted in a threefold increase in the survival of lethal glycerol-treated mice. The post-administration of HSA-Trx at 1 and 3 hr after glycerol injection exerted a significant renoprotective effect. These results suggest HSA-Trx has potential for use in the treatment of rhabdomyolysis-associated AKI via its extended effects of modulating oxidative stress and MIF.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ogaki
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Kodama
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Imafuku
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth 6845, WA, Australia.
authors.forename: Victor Tuan Giam
authors.initials: VT
authors.lastname: Chuang
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Kondoh
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1, Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.|DDS Research Institute, Sojo University, 4-22-1, Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005990:Glycerol / Q000009:adverse effects; D018836:Inflammation Mediators / Q000378:metabolism; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009211:Myoglobin / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012206:Rhabdomyolysis / Q000150:complications*; D013879:Thioredoxins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D009211:Myoglobin; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D005990:Glycerol