BET Protein Inhibitor JQ1 Modulates Mitochondrial Dysfunction and Oxidative Stress Induced by Chronic Kidney Disease

Abstract

Among the mechanisms involved in the progression of kidney disease, mitochondrial dysfunction has special relevance. Epigenetic drugs such as inhibitors of extra-terminal domain proteins (iBET) have shown beneficial effects in experimental kidney disease, mainly by inhibiting proliferative and inflammatory responses. The impact of iBET on mitochondrial damage was explored in in vitro studies in renal cells stimulated with TGF-β1 and in vivo in murine unilateral ureteral obstruction (UUO) model of progressive kidney damage. In vitro, JQ1 pretreatment prevented the TGF-β1-induced downregulation of components of the oxidative phosphorylation chain (OXPHOS), such as cytochrome C and CV-ATP5a in human proximal tubular cells. In addition, JQ1 also prevented the altered mitochondrial dynamics by avoiding the increase in the DRP-1 fission factor. In UUO model, renal gene expression levels of cytochrome C and CV-ATP5a as well as protein levels of cytochrome C were reduced These changes were prevented by JQ1 administration. In addition, JQ1 decreased protein levels of the DRP1 fission protein and increased the OPA-1 fusion protein, restoring mitochondrial dynamics. Mitochondria also participate in the maintenance of redox balance. JQ1 restored the gene expression of antioxidant proteins, such as Catalase and Heme oxygenase 1 in TGF-β1-stimulated human proximal tubular cells and in murine obstructed kidneys. Indeed, in tubular cells, JQ1 decreased ROS production induced by stimulation with TGF-β1, as evaluated by MitoSOXTM. iBETs, such as JQ1, improve mitochondrial dynamics, functionality, and oxidative stress in kidney disease.