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Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Secukinumab Mitigates Cisplatin-Induced Nephrotoxicity and Enhances Cisplatin Cytotoxicity in MCF-7 Cells via
Faiz N Alenezi1, Marwa S Zaghloul1,2, Manar A Nader1,2
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Objective:
The existing work was designed to appraise whether Secukinumab diminishes acute kidney injury in a Cisplatin- induced rat model and to explore the potential underlying mechanisms for this protective effect.
Methods:
In vivo study, rats were distributed haphazardly into five sets (six animals in each group): control, Secukinumab control, Cisplatin (8 mg/kg, a single dose, intraperitoneally (IP)), and two pretreated groups; Secukinumab (10 and 20 mg/kg single subcutaneous (SC) injection) + Cisplatin. Blood samples and kidney tissues were gathered and analyzed histopathologically and biochemically. In vitro investigation, MCF-7 human breast cancer cells were treated with Cisplatin alone with Secukinumab, and cell viability (MTT assay), combination index, and apoptosis-related markers were analyzed.
Results:
Secukinumab administration lowered serum levels of BUN, creatinine and LDH with marked elevation in renal TAC and a significant reduction in MDA, iNOS, KIM-1 and NGAL compared to Cisplatin. Additionally, Secukinumab pre-treatment markedly suppressed the inflammatory process and enhanced autophagy, reflected by elevated AMPKα1, SIRT1, and Beclin-1, accompanied by reduced P38 MAPK and NF-κB p65 (Phospho-Ser536) levels and expression levels of IL-6 and P62/SQSTM1 in kidney tissues, contrasted with the Cisplatin group. Secukinumab administration effectively protected against kidney injury, and histopathological examinations of the kidneys confirmed these results. On the other hand, in vitro study results revealed that the combination of Cisplatin and Secukinumab had a synergistic cytotoxic effect and an enhancing effect on the apoptotic pathway (increased P53 and BAX and decreased BCL-2). Secukinumab effectively protects against Cisplatin- induced acute kidney injury by decreasing oxidative stress, inflammation, and enhancing autophagy. Additionally, it synergizes with Cisplatin in vitro to promote cancer cell apoptosis, highlighting its dual reno-protective and anticancer potential.
Insights
Secukinumab protects against cisplatin-induced acute kidney injury by reducing oxidative stress and inflammation. It also enhances autophagy and synergizes with cisplatin to promote cancer cell apoptosis, showing dual reno-protective and anticancer potential.
Area of Science:
- Nephrology
- Pharmacology
- Oncology
Background:
- Cisplatin chemotherapy can cause acute kidney injury (AKI).
- Identifying protective agents against cisplatin-induced AKI is crucial for patient management.
- Secukinumab's potential reno-protective effects warrant investigation.
Purpose of the Study:
- To evaluate Secukinumab's efficacy in preventing cisplatin-induced AKI in a rat model.
- To elucidate the underlying mechanisms of Secukinumab's protective action.
- To assess the in vitro synergistic effect of Secukinumab and cisplatin on cancer cells.
Main Methods:
- In vivo: Rats received cisplatin with or without Secukinumab; kidney function and tissue were analyzed.
- In vitro: MCF-7 breast cancer cells were treated with cisplatin and Secukinumab to assess cytotoxicity and apoptosis.
- Biochemical assays, histopathology, and molecular markers for inflammation, oxidative stress, and autophagy were employed.
Main Results:
- Secukinumab significantly reduced serum BUN, creatinine, and LDH, while increasing renal antioxidant capacity (TAC).
- It suppressed inflammation (reduced iNOS, NF-κB, IL-6) and oxidative stress (reduced MDA), and enhanced autophagy (increased AMPKα1, SIRT1, Beclin-1).
- In vitro, Secukinumab and cisplatin showed synergistic cytotoxicity and enhanced apoptosis in cancer cells.
Conclusions:
- Secukinumab effectively protects against cisplatin-induced acute kidney injury.
- Mechanisms include decreased oxidative stress, inflammation, and enhanced autophagy.
- Secukinumab demonstrates potential as a dual agent for reno-protection and cancer therapy.
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