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

作者：Kodama Azusa; Watanabe Hiroshi; Tanaka Ryota; Kondo Masumi; Victor Tuan Giam Chuang; Wu Qiong; Endo Masayuki; Ishima Yu; Fukagawa Masafumi; Otagiri Masaki; Maruyama Toru^*

来源：Biochimica et Biophysica Acta-General Subjects, 2014, 1840(3): 1152-1162.

DOI：10.1016/j.bbagen.2013.12.007

• Acute kidney injury
• Cisplatin nephrotoxicity
• Oxidative stress
• Inflammation
• Thioredoxin
• Fusion protein

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. %26lt;br%26gt;Methods: HSA-Trx was prepared in Pichia expression system. Cisplatin-induced nephropathy mouse model was established by a single administration of cisplatin. %26lt;br%26gt;Results: Compared to saline, Trx or N-acetylcysteine, an intravenous administration of HSA-Tix attenuated the cisplatin-induced elevation in serum creatinine, blood urea nitrogen and urinary N-acetyl-beta-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-alpha, IL-1 beta 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. %26lt;br%26gt;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. %26lt;br%26gt;General signcance: We report the renoprotective effect of HSA-Trx against cisplatin nephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatin nephrotoxicity.

• 出版日期2014-3