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

• Published in: Biochimica et biophysica acta Vol. 1840; no. 3; pp. 1152 - 1162
• Main Authors: Kodama, Azusa, Watanabe, Hiroshi, Tanaka, Ryota, Kondo, Masumi, Chuang, Victor Tuan Giam, Wu, Qiong, Endo, Masayuki, Ishima, Yu, Fukagawa, Masafumi, Otagiri, Masaki, Maruyama, Toru
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2014
• Subjects: acetylcysteine; Acute kidney injury; albumins; animal models; Animals; anti-inflammatory activity; anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Antineoplastic Agents - toxicity; Antioxidants - pharmacology; Apoptosis - drug effects; beta-N-acetylhexosaminidase; blood circulation; blood serum; cisplatin; Cisplatin - toxicity; Cisplatin nephrotoxicity; creatinine; fluorescein; Fusion protein; glutathione; Humans; Inflammation; interleukin-1beta; interleukin-6; intravenous injection; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; kidney diseases; kidneys; Male; Mice; Mice, Inbred ICR; nephrotoxicity; Oxidative stress; Pichia; reactive oxygen species; Reactive Oxygen Species - metabolism; renoprotective effect; Serum Albumin - metabolism; Serum Albumin - pharmacology; Thioredoxin; Thioredoxins - metabolism; Thioredoxins - pharmacology; tumor necrosis factor-alpha; urea nitrogen; Oxidative stress; Inflammation; Thioredoxin; Fusion protein; Acute kidney injury; Cisplatin nephrotoxicity
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.12.007

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. •Human serum albumin-thioredoxin (HSA-Trx) was produced by recombinant HSA fusion.•Pretreatment of a single dose of HSA-Trx prevents cisplatin nephrotoxicity.•Preventive effect of HSA-Trx is due to reducing oxidative stress and inflammation.•HSA-Trx functions inside the tubular cells as well as in the blood circulation.