Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
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Elsevier BV
2014
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| Online Access: | http://hdl.handle.net/20.500.11937/26865 |
| _version_ | 1848752107215126528 |
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| author | Kodama, A. Watanabe, H. Tanaka, R. Kondo, M. Chuang, Victor Wu, Q. Endo, M. Ishima, Y. Fukagawa, M. Otagiri, M. Maruyama, T. |
| author_facet | Kodama, A. Watanabe, H. Tanaka, R. Kondo, M. Chuang, Victor Wu, Q. Endo, M. Ishima, Y. Fukagawa, M. Otagiri, M. Maruyama, T. |
| author_sort | Kodama, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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-Trx attenuated the cisplatin-induced elevation in serum creatinine, blood urea nitrogen and urinary N-acetyl-ß-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-a, IL-1ß 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 significance: We report the renoprotective effect of HSA-Trx against cisplatin nephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatin nephrotoxicity. |
| first_indexed | 2025-11-14T08:03:21Z |
| format | Journal Article |
| id | curtin-20.500.11937-26865 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:03:21Z |
| publishDate | 2014 |
| publisher | Elsevier BV |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-268652017-09-13T16:08:58Z Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity Kodama, A. Watanabe, H. Tanaka, R. Kondo, M. Chuang, Victor Wu, Q. Endo, M. Ishima, Y. Fukagawa, M. Otagiri, M. Maruyama, T. Thioredoxin Oxidative stress Acute kidney injury Cisplatin nephrotoxicity Fusion protein Inflammation 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-Trx attenuated the cisplatin-induced elevation in serum creatinine, blood urea nitrogen and urinary N-acetyl-ß-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-a, IL-1ß 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 significance: We report the renoprotective effect of HSA-Trx against cisplatin nephrotoxicity. This work would enhance developing therapeutics against acute kidney injuries including cisplatin nephrotoxicity. 2014 Journal Article http://hdl.handle.net/20.500.11937/26865 10.1016/j.bbagen.2013.12.007 Elsevier BV restricted |
| spellingShingle | Thioredoxin Oxidative stress Acute kidney injury Cisplatin nephrotoxicity Fusion protein Inflammation Kodama, A. Watanabe, H. Tanaka, R. Kondo, M. Chuang, Victor Wu, Q. Endo, M. Ishima, Y. Fukagawa, M. Otagiri, M. Maruyama, T. Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title | Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title_full | Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title_fullStr | Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title_full_unstemmed | Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title_short | Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| title_sort | albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity |
| topic | Thioredoxin Oxidative stress Acute kidney injury Cisplatin nephrotoxicity Fusion protein Inflammation |
| url | http://hdl.handle.net/20.500.11937/26865 |