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

被引：64

作者：

Kodama, Azusa ^{[1
]}

Watanabe, Hiroshi ^{[1
,2
]}

Tanaka, Ryota ^{[1
]}

Kondo, Masumi ^{[3
]}

Victor Tuan Giam Chuang ^{[4
]}

Wu, Qiong ^{[3
]}

Endo, Masayuki ^{[3
]}

Ishima, Yu ^{[1
,2
]}

Fukagawa, Masafumi ^{[3
]}

Otagiri, Masaki ^{[5
,6
]}

Maruyama, Toru ^{[1
,2
]}

机构：

[1] Kumamoto Univ, Sch Pharm, Grad Sch Pharmaceut Sci, Dept Biopharmaceut,Chuo Ku, Kumamoto 8620973, Japan

[2] Kumamoto Univ, Sch Pharm, Ctr Clin Pharmaceut Sci, Chuo Ku, Kumamoto 8620973, Japan

[3] Tokai Univ, Sch Med, Div Nephrol Endocrinol & Metab, Hiratsuka, Kanagawa 25912, Japan

[4] Curtin Univ, Curtin Hlth Innovat Res Inst, Fac Hlth Sci, Sch Pharm, Perth, WA 6845, Australia

[5] Sojo Univ, Fac Pharmaceut Sci, Nishi Ku, Kumamoto 8600822, Japan

[6] Sojo Univ, DDS Res Inst, Nishi Ku, Kumamoto 8600822, Japan

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2014年 / 1840卷 / 03期

基金：

日本学术振兴会;

关键词：

Acute kidney injury; Cisplatin nephrotoxicity; Oxidative stress; Inflammation; Thioredoxin; Fusion protein; ACUTE-RENAL-FAILURE; SERUM-ALBUMIN; LUNG INJURY; PROTEIN; RATS; RADICALS; ACTIVATION; APOPTOSIS; TRANSPORT; FIBROSIS;

D O I：

10.1016/j.bbagen.2013.12.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1152 / 1162

页数：11

共 41 条

[1]

N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity [J].