Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae

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Padovani, Barbara Nunes ; Fenero, Camila Morales ; Paredes, Lais Cavalieri ; do Amaral, Mariana Abrantes ; Dominguez-Amorocho, Omar ; Cipelli, Marcella ; Gomes, Juliana Moreira Mendonca ; da Silva, Eloisa Martins ; Silva, Luisa Menezes ; de Souza Vieira, Raquel ; Pereira, Mariana Tominaga ; Cruz, Mario Costa ; Camara, Niels Olsen Saraiva

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 25, n. 4, p. 16-pg., 2024-02-01.

Abstract

Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish (Danio rerio), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12, il6, and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils. (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/21644-9 - Obesity-induced inflammation, alterations in the microbiota and their effects on the enteric nervous system: study in an experimental model of zebrafish.
• Grantee: Camila Idelí Morales Fénero
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/12833-6 - Effect of caloric restriction on cGAS-STING signaling on Acute Kidney Injury in Zebrafish
• Grantee: Barbara Nunes Padovani
• Support Opportunities: Scholarships in Brazil - Doctorate