Deacetylase Inhibitor Trichostatin A Promotes the Proliferation of Epithelial Cells and Suppresses Glycolytic Activity of Fibroblasts in the Kidney

Abstract

Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expression profiles, including metabolism-related genes. As a result, these cell types exhibit differences in the energy metabolism that could be the basis of targeted therapy for fibrosis. Among other deacetylase inhibition is considered a therapeutic approach that could simultaneously promote tissue regeneration and suppress the development of fibrosis, but their relation to bioenergetics has not been considered before. In this study, we aimed to compare the influence of the HDAC inhibitor trichostatin A (TSA) on renal tubular epithelial cells and kidney fibroblasts. We analyzed resemblance and differences in TSA effects on the proliferative activity of the cells and investigated the molecular mechanisms responsible for these effects; e.g., we focused on the activity of signaling pathways associated with cell viability (Akt/mTOR/p70^S6). We found that TSA increased the proliferation rate of epithelial cells, while it tended to decrease the growth rate of fibroblasts. Furthermore, the amount of phosphorylated forms of kinases Akt and P70^S6 increased in epithelial cells after incubation with TSA, indicating the activation of the Akt/mTOR/p70^S6 signaling pathway, while decreasing its activity in fibroblast cells. Since there are differences in the bioenergetics between fibroblasts and epithelial cells, we investigated the impact of TSA on the glycolytic activity of both cell types. Indeed, we showed that TSA reduced the activity of glycolytic processes in fibroblast cells. The observed changes indicate a positive effect of TSA on regenerative versus fibrotic processes in the kidney by reducing the growth and metabolic activity of fibroblasts and activating the proliferation of epithelial cells.