Azusa Kodama1, Hiroshi Watanabe2, Ryota Tanaka1, Masumi Kondo3, Victor Tuan Giam Chuang4, Qiong Wu3, Masayuki Endo3, Yu Ishima2, Masafumi Fukagawa3, Masaki Otagiri5, Toru Maruyama6. 1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. 2. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, School of Pharmacy, 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. 3. Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan. 4. School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6845, Western Australia, Australia. 5. Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0822, Japan; DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0822, Japan. 6. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, School of Pharmacy, 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. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
Abstract
BACKGROUND: A strategy for preventing cisplatin nephrotoxicity due to enhanced oxidative stress and inflammatory response is highly desirable. Thioredoxin-1 (Trx), an endogenous redox-active protein, has a short retention time in the blood. A long acting form of Trx, human serum albumin-Trx (HSA-Trx), was produced by recombinant HSA fusion and its effectiveness in preventing cisplatin nephrotoxicity was examined. METHODS: HSA-Trx was prepared in Pichia expression system. Cisplatin-induced nephropathy mouse model was established by a single administration of cisplatin. RESULTS: Compared to saline, Trx or N-acetylcysteine, an intravenous administration of HSA-Trx attenuated the cisplatin-induced elevation in serum creatinine, blood urea nitrogen and urinary N-acetyl-β-d-glucosaminidase along with the decrease in creatinine clearance. HSA-Trx caused a substantial reduction in the histological features of renal tubular injuries and the apoptosis-positive tubular cells. Changes in superoxide, 8-OHdG, glutathione and nitrotyrosine levels indicated that HSA-Trx significantly suppressed renal oxidative stress. HSA-Trx also suppressed the elevation of TNF-α, IL-1β and IL-6. Administered fluorescein isothiocyanate-labeled HSA-Trx was found partially localized in the proximal tubular cells whereas majority remained in the blood circulation. Specific cellular uptake and the scavenging of intracellular reactive oxygen species by HSA-Trx were observed in HK-2 cells. CONCLUSION: HSA-Trx could be a novel and effective approach for preventing cisplatin nephrotoxicity due to its prolonged anti-oxidative and anti-inflammatory action not only in extracellular compartment but also inside the proximal tubular cell. GENERAL SIGNIFICANCE: We report the renoprotective effect of HSA-Trx against cisplatin nephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatin nephrotoxicity.
BACKGROUND: A strategy for preventing cisplatinnephrotoxicity due to enhanced oxidative stress and inflammatory response is highly desirable. Thioredoxin-1 (Trx), an endogenous redox-active protein, has a short retention time in the blood. A long acting form of Trx, human serum albumin-Trx (HSA-Trx), was produced by recombinant HSA fusion and its effectiveness in preventing cisplatinnephrotoxicity was examined. METHODS: HSA-Trx was prepared in Pichia expression system. Cisplatin-induced nephropathymouse model was established by a single administration of cisplatin. RESULTS: Compared to saline, Trx or N-acetylcysteine, an intravenous administration of HSA-Trx attenuated the cisplatin-induced elevation in serum creatinine, blood ureanitrogen and urinary N-acetyl-β-d-glucosaminidase along with the decrease in creatinine clearance. HSA-Trx caused a substantial reduction in the histological features of renal tubular injuries and the apoptosis-positive tubular cells. Changes in superoxide, 8-OHdG, glutathione and nitrotyrosine levels indicated that HSA-Trx significantly suppressed renal oxidative stress. HSA-Trx also suppressed the elevation of TNF-α, IL-1β and IL-6. Administered fluorescein isothiocyanate-labeled HSA-Trx was found partially localized in the proximal tubular cells whereas majority remained in the blood circulation. Specific cellular uptake and the scavenging of intracellular reactive oxygen species by HSA-Trx were observed in HK-2 cells. CONCLUSION: HSA-Trx could be a novel and effective approach for preventing cisplatinnephrotoxicity due to its prolonged anti-oxidative and anti-inflammatory action not only in extracellular compartment but also inside the proximal tubular cell. GENERAL SIGNIFICANCE: We report the renoprotective effect of HSA-Trx against cisplatinnephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatinnephrotoxicity.