Rayego-Mateos Sandra, Basantes Pamela, Morgado-Pascual José Luis, Brazal Prieto Beatriz, Suarez-Alvarez Beatriz, Ortiz Alberto, Lopez-Larrea Carlos, Ruiz-Ortega Marta
Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain.
Ricors2040, 28029 Madrid, Spain.
Antioxidants (Basel). 2023 May 20;12(5):1130. doi: 10.3390/antiox12051130.
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.
在肾脏疾病进展所涉及的机制中，线粒体功能障碍具有特殊的相关性。表观遗传药物，如末端外结构域蛋白抑制剂（iBET），在实验性肾脏疾病中已显示出有益作用，主要是通过抑制增殖和炎症反应。在体外研究中，用转化生长因子-β1（TGF-β1）刺激肾细胞，并在体内采用小鼠单侧输尿管梗阻（UUO）进行渐进性肾损伤模型，探讨了iBET对线粒体损伤的影响。在体外，JQ1预处理可防止TGF-β1诱导的人近端肾小管细胞中氧化磷酸化链（OXPHOS）成分（如细胞色素C和CV-ATP5a）的下调。此外，JQ1还通过避免动力相关蛋白1（DRP-1）裂变因子的增加来防止线粒体动力学改变。在UUO模型中，细胞色素C和CV-ATP5a的肾脏基因表达水平以及细胞色素C的蛋白水平均降低，而JQ1给药可防止这些变化。此外，JQ1降低了DRP1裂变蛋白的水平，并增加了视神经萎缩蛋白1（OPA-1）融合蛋白，恢复了线粒体动力学。线粒体还参与氧化还原平衡的维持。JQ1恢复了抗氧化蛋白的基因表达，如在TGF-β1刺激的人近端肾小管细胞和小鼠梗阻肾脏中的过氧化氢酶和血红素加氧酶1。实际上，在肾小管细胞中，通过MitoSOXTM评估，JQ1减少了TGF-β1刺激诱导的活性氧（ROS）产生。iBETs，如JQ1，可改善肾脏疾病中的线粒体动力学、功能和氧化应激。
