Modulação da expressão gênica renal mediada por cisplatina: uma visão integrativa entre genes e transcritos codificadores e não codificadores de proteínas

Abstract

Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors and has in nephrotoxicity its greatest limitation. Despite efforts, the mechanisms of toxicity are not yet completely elucidated. In this work, the modulation of gene expression was evaluated in the kidneys of mice treated with cisplatin using publicly available data in the Gene Expression Omnibus (GEO) under access numbers GSE69652 and GSE106993. Briefly, the mice were treated with cisplatin or saline (control). At the end of the treatment, the animals were euthanized and the kidneys were removed, then the RNA was extracted and sequenced. Differential transcript expression analysis identified an increase in the cellular response to DNA damage, especially related to apoptosis by intrinsic pathways and a decrease in the expression of genes related to cellular basal metabolisms, such as amino acid and fatty acid metabolism. The analysis at the level of transcripts revealed a change in alternative splicing patterns, where coding genes expressed transcripts in their coding and non-coding protein isoforms. The differential expression also revealed changes in dozens of long non-coding RNAs (lncRNA). The identification of these lncRNAs added new information to the mechanisms of regulation of cell death by apoptosis and inflammation resulting from cisplatin-induced nephrotoxicity. Together, the expression of the lincRNA-p21 and Gm26917 lncRNAs and non-coding isoforms of the Mdm2 protein-coding gene, revealed strong negative regulation of Mdm2, despite the overexpression of this gene, culminating in the maintenance of apoptosis. For the first time, readthrough transcription, which occurs when transcription continues after the termination site, is being reported in cisplatin-induced nephrotoxicity. The genes that have undergone readthrough transcription are involved in the processing of mRNA. Evidence that the RNAs of genes undergoing readthrough transcription are not translated shows that this type of transcription may be related to the modulation of splicing due to treatment with cisplatin.