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Updated: Oct 21, 2025
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Pevonedistat attenuates cisplatin-induced nephrotoxicity in mice by downregulating the release of inflammatory
Yousra M El-Far1, Mohamed El-Mesery1
1Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Abstract:
Pevonedistat (MLN4924) is a specific NEDD8-activating enzyme inhibitor that inactivates cullin-RING ligases involved in ubiquitylation and turnover of different signaling molecules. In the current study, we evaluated the effect of pevonedistat on cisplatin (CIS)-induced nephrotoxicity in mice. Serum creatinine and urea levels were analyzed in different groups. Histopathological examination of renal tissue was done using hematoxylin and eosin staining. In addition, renal IL-6 and TNF-α expressions were analyzed using the enzyme-linked immunosorbent assay technique, and IL-1β and NF-κB expressions were analyzed by immunohistochemical staining of renal tissue. Caspase-3, A20, β-catenin, and Nrf2 gene expressions in renal tissue were analyzed using the reverse-transcription polymerase chain reaction technique. Western blot analysis was adopted to assess cleaved caspase-3 and β-catenin expressions in renal tissue. Pevonedistat coadministration with CIS improved kidney functions and attenuated CIS-induced nephrotoxicity as indicated by the significant decrease in serum creatinine and urea levels. In addition, pevonedistat coadministration with CIS showed a significant decrease in caspase-3 and a significant increase in A20, β-catenin, and Nrf2 gene expressions. Also, pevonedistat decreased caspase-3 cleavage to p19 in mice treated with CIS. Moreover, pevonedistat decreased CIS-induced upregulation of IL-6, TNF-α, IL-1β, and NF-κB protein expressions in renal tissue. Thus, pevonedistat alleviated CIS-induced nephrotoxicity that might be attributed to suppression of the inflammation induced in renal tissue.
Insights
Pevonedistat protects against cisplatin-induced kidney damage by reducing inflammation and improving kidney function. This study shows pevonedistat (MLN4924) as a potential therapeutic agent for mitigating nephrotoxicity.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Cisplatin (CIS) is a widely used chemotherapy agent with significant nephrotoxicity.
- Pevonedistat (MLN4924) is a novel inhibitor of NEDD8-activating enzyme, targeting cullin-RING ligases.
- Understanding mechanisms to mitigate CIS-induced kidney damage is crucial for cancer therapy.
Purpose of the Study:
- To investigate the protective effects of pevonedistat against cisplatin-induced nephrotoxicity in a mouse model.
- To elucidate the molecular mechanisms underlying pevonedistat's renoprotective action.
Main Methods:
- Mice were treated with cisplatin alone or in combination with pevonedistat.
- Kidney function was assessed by measuring serum creatinine and urea levels.
- Renal histopathology, inflammatory markers (IL-6, TNF-α, IL-1β, NF-κB), apoptosis (caspase-3), and key signaling pathways (A20, β-catenin, Nrf2) were analyzed using various techniques including ELISA, immunohistochemistry, RT-PCR, and Western blot.
Main Results:
- Pevonedistat coadministration significantly improved kidney function, reducing serum creatinine and urea levels.
- Histopathological examination revealed attenuated renal damage in mice treated with pevonedistat and cisplatin.
- Pevonedistat decreased apoptosis markers (caspase-3 cleavage) and suppressed inflammatory cytokine and transcription factor expressions (IL-6, TNF-α, IL-1β, NF-κB).
- Pevonedistat upregulated protective genes including A20, β-catenin, and Nrf2.
Conclusions:
- Pevonedistat effectively alleviates cisplatin-induced nephrotoxicity in mice.
- The renoprotective effects are associated with the suppression of inflammation, apoptosis, and modulation of key cellular pathways.
- Pevonedistat demonstrates potential as a therapeutic strategy to mitigate chemotherapy-induced kidney injury.
