Role of Histone deacetylases in NF-kB pathway signaling in cisplatin-induced liver and kidney injuries in zebrafish

Abstract

Cisplatin, a drug used for solid cancer treatment, has as side effects the nephrotoxicity and hepatotoxicity, consequences of injuries induced by the drug, mainly from the release of reactive oxygen species caused by the attack on the CYP450 enzymatic complex. Thus, this project aims to study kidney and hepatic damage caused by this drug through the analysis of the autophagy mechanism associated with the canonical NF-kB pathway signaling. In this regard, we formulated the hypothesis that the histone deacetylase inhibitors will increase autophagy process and, from the degradation of IKK5ý, decrease this pathway activation and, consequently, lead to immunosuppression. The inhibitors that will be tested in this project are trichostatin A and valproic acid, responsible for the inhibition of histone deacetylation, promoting less chromatin compaction and more permissiveness of the genetic material to transcriptional machinery. Our laboratory has used the zebrafish (Danio rerio) as an organism model for injuries because it has the advantage of having genetic compatibility and anatomical similarity with the human. Based on that, in an unprecedented way, this project anticipates the establishment and standardization of the culture of primary cells from adult zebrafish kidney. Besides, the immortalized lineage Zebrafish Liver Cells (ZFLs) will be used for analysis of liver injury, using the wide use of this culture for studies of toxicology and human diseases simulation. Thus, in the end, it will be possible to define a cisplatin minimum concentration that induces nephrotoxicity and hepatotoxicity and, therefore, create in vitro injury models. Finally, with the protective effect of HDACi in this animal model, it will be possible to study how to reduce the side effects of cisplatin and improve the patient's life quality already weakened by cancer.