期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1840, 期 3, 页码 1152-1162出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2013.12.007
关键词
Acute kidney injury; Cisplatin nephrotoxicity; Oxidative stress; Inflammation; Thioredoxin; Fusion protein
资金
- Japan Society for the Promotion of Science (JSPS) [KAKENHI 21390177]
- Grants-in-Aid for Scientific Research [25670085] Funding Source: KAKEN
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-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. 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 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. (C) 2013.Elsevier B.V. All rights reserved.
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