Abstract：
The inhibition of the autophagolysosomal pathway mediated by transcription factor EB (TFEB) inactivation in proximal tubular epithelial cells (TECs) is a key mechanism of TEC injury in diabetic kidney disease (DKD). Acetylation is a novel mechanism that regulates TFEB activity. However, there are currently no studies on whether the adjustment of the acetylation level of TFEB can reduce the damage of diabetic TECs. In this study, we investigated the effect of Trichostatin A (TSA), a typical deacetylase inhibitor, on TFEB activity and damage to TECs in both in vivo and in vitro models of DKD. Here, we show that TSA treatment can alleviate the pathological damage of glomeruli and renal tubules and delay the DKD progression in db/db mice, which is associated with the increased expression of TFEB and its downstream genes. In vitro studies further confirmed that TSA treatment can upregulate the acetylation level of TFEB, promote its nuclear translocation, and activate the expression of its downstream genes, thereby reducing the apoptosis level of TECs. TFEB deletion or HDAC6 knockdown in TECs can counteract the activation effect of TSA on autophagolysosomal pathway. We also found that TFEB enhances the transcription of Tfeb through binding to its promoter and promotes its own expression. Our results, thus, provide a novel therapeutic mechanism for DKD that the alleviation of TEC damage by activating the autophagic lysosomal pathway through upregulating TFEB acetylation can, thus, delay DKD progression.
摘要：
近端肾小管上皮细胞（TECs）转录因子EB（TFEB）失活介导的自噬溶酶体途径的抑制是糖尿病肾病（DKD）TEC损伤的关键机制。乙酰化是调节TFEB活性的新机制。然而,目前尚无关于调整TFEB乙酰化水平是否能降低糖尿病TECs损伤的研究。在这项研究中,我们研究了曲古抑菌素A（TSA）的作用，典型的脱乙酰酶抑制剂，在DKD的体内和体外模型中TFEB活性和对TECs的损伤。这里,我们表明TSA治疗可以减轻db/db小鼠肾小球和肾小管的病理损伤，延缓DKD的进展，这与TFEB及其下游基因的表达增加有关。体外研究进一步证实，TSA处理可以上调TFEB的乙酰化水平，促进其核易位，并激活其下游基因的表达，从而降低TECs的凋亡水平。TECs中的TFEB缺失或HDAC6敲低可以抵消TSA对自噬溶酶体途径的激活作用。我们还发现TFEB通过结合其启动子增强Tfeb的转录并促进其自身的表达。我们的结果,因此，为DKD提供了一种新的治疗机制，即通过上调TFEB乙酰化激活自噬溶酶体途径来减轻TEC损伤，因此，延迟DKD进展。
