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Updated: Jun 1, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a
Cheng Tien Wu1, Meei Ling Sheu, Keh Sung Tsai
1Institute of Toxicology, National Taiwan University College of Medicine, Taipei 10043, Taiwan.
Abstract:
Although cisplatin attacks various tumors with remarkable efficacy, its clinical usage has been limited by its side effects, particularly nephrotoxicity. Salubrinal, a selective eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation inhibitor, has been found to protect cells from endoplasmic reticulum (ER)-stress-induced cytotoxicity. In this study, we hypothesized that salubrinal would protect against cisplatin-induced nephrotoxicity in a mouse model. Cisplatin treatment significantly increased serum blood urea nitrogen and creatinine levels, renal kidney injury marker (kim-1) mRNA expression, renal cell apoptosis, and renal histopathological changes in mice. Unexpectedly, administration of salubrinal significantly enhanced the cisplatin-induced nephrotoxicity in mice. Salubrinal by itself did not induce alterations in the function or histomorphology of mouse kidneys. Salubrinal significantly enhanced the phosphorylation of eIF2α, the protein expression of activating transcription factor 4 and CCAAT/enhancer binding protein homologous protein, and the cleavage of caspases 12, 9, and 3 in the kidneys of cisplatin-treated mice. Moreover, salubrinal enhanced the cisplatin-induced oxidative stress in the kidneys. The antioxidant N-acetylcysteine significantly reversed the increased renal lipid peroxidation, activated renal caspase cascade, and increased blood BUN and creatinine in cisplatin-alone- or cisplatin plus salubrinal-treated mice. These findings suggest that salubrinal aggravates cisplatin-induced nephrotoxicity through the enhancement of oxidative stress and ER stress-related cell apoptosis.
Insights
Salubrinal, a drug intended to protect cells, unexpectedly worsened kidney damage caused by cisplatin chemotherapy in mice. This enhancement of cisplatin nephrotoxicity was linked to increased oxidative and endoplasmic reticulum stress.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Cisplatin is an effective chemotherapy drug but causes significant kidney damage (nephrotoxicity).
- Salubrinal inhibits dephosphorylation of eukaryotic translation initiation factor 2 subunit α (eIF2α) and protects against endoplasmic reticulum (ER) stress.
Purpose of the Study:
- To investigate the potential protective effect of salubrinal against cisplatin-induced nephrotoxicity in a mouse model.
Main Methods:
- Mice were treated with cisplatin alone or in combination with salubrinal.
- Kidney function was assessed by measuring serum blood urea nitrogen (BUN) and creatinine.
- Renal injury markers, apoptosis, oxidative stress, and ER stress pathways were analyzed.
Main Results:
- Salubrinal significantly aggravated cisplatin-induced nephrotoxicity, increasing BUN, creatinine, and kidney injury marker 1 (kim-1) expression.
- Salubrinal enhanced cisplatin-induced renal cell apoptosis, oxidative stress, and ER stress markers (eIF2α phosphorylation, ATF4, CHOP).
- The antioxidant N-acetylcysteine reversed the enhanced nephrotoxicity caused by cisplatin and salubrinal.
Conclusions:
- Salubrinal exacerbates cisplatin-induced nephrotoxicity, contrary to expectations.
- This detrimental effect is mediated by enhanced oxidative stress and ER stress-induced apoptosis in the kidneys.
- Targeting oxidative stress may be a therapeutic strategy to mitigate cisplatin-induced kidney damage.
