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Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity

Kodama, Azusa, Watanabe, Hiroshi, Tanaka, Ryota, Kondo, Masumi, Chuang, Victor Tuan Giam, Wu, Qiong, Endo, Masayuki, Ishima, Yu, Fukagawa, Masafumi, Otagiri, Masaki, Maruyama, Toru
BBA - General Subjects 2014 v.1840 pp. 1152-1162
Pichia, acetylcysteine, albumins, animal models, anti-inflammatory activity, anti-inflammatory agents, beta-N-acetylhexosaminidase, blood circulation, blood serum, cisplatin, creatinine, fluorescein, glutathione, humans, inflammation, interleukin-1beta, interleukin-6, intravenous injection, kidney diseases, kidneys, nephrotoxicity, oxidative stress, reactive oxygen species, renoprotective effect, therapeutics, tumor necrosis factor-alpha, urea nitrogen
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.HSA-Trx was prepared in Pichia expression system. Cisplatin-induced nephropathy mouse model was established by a single administration of cisplatin.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.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.We report the renoprotective effect of HSA-Trx against cisplatin nephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatin nephrotoxicity.