T-cell-restricted intracellular antigen 1 regulates the expression and alternative splicing of stress-related genes in human renal tubular epithelial cells

Abstract

Abstract Understanding the mechanisms mediating secondary nonimmune renal injury in lupus nephritis (LN) is important for therapeutic development. Cytotoxic granule-associated RNA-binding protein 1 (T-cell-resrticted intracellular antigen 1, TIA1) plays potential roles in infiltrating immune cells in LN. However, the regulatory targets and mechanisms underlying TIA1 activity in renal nonimmune cells remain unclear. Here, TIA1 was overexpressed in a human renal tubular epithelial cell line (HK-2). Then, RNA sequencing and bioinformatic analysis were performed to compare the expression profile and alternative splicing pattern in TIA1-overexpressing (TIA1-OE) and control cells. Additionally, the expression of Tia1 and the genes that it may regulate in the kidney tissues of LN mice was analysed. The results showed TIA1-OE increased and decreased the transcript levels of 101 and 452 genes in HK-2 cells, respectively. Gene Ontology (GO)analysis showed that the downregulated genes were significantly enriched in several terms associated with the cellular response to stress. Moreover, TIA1-OE changed the pattern of 2,035 alternative splicing events that occurred in 1,420 genes in HK-2 cells. GO analysis showed t genes were significantly enriched in DNA repair and cellular response to DNA damage stimulus terms. These results demonstrate that TIA1 mediates secondary nonimmune renal injury by regulating the expression and alternative splicing of stress-related genes in renal tubular epithelial cells, which provides a reference for targeted therapy for renal injury in LN.