TFEB/ZKSCAN3平衡失调所致溶酶体更新障碍在糖尿病肾病肾小管上皮细胞损伤中的作用

我们前期研究发现：糖尿病（DM）状态下肾小管上皮细胞（TEC）溶酶体功能耗竭引起的自噬通路阻滞导致了TEC损伤，因此，促进TEC溶酶体更新以疏通自噬通路对延缓糖尿病肾病（DN）进展意义重大，但仍缺乏有效干预手段。我们预实验发现，DM状态下TEC溶酶体生源不足伴随促自噬及溶酶体相关基因转录的TFEB表达下降，而抑制这些基因转录的ZKSCAN3表达却升高，推测两者以相反方向协同发挥对自噬和溶酶体生源及功能调节。本研究拟首先验证TFEB/ZKSCAN3失平衡所致自噬及溶酶体相关基因转录共调节失衡可能是导致DM状态下TEC溶酶体生源不足、更新障碍及细胞损伤的重要机制，并继之在经典mTOR抑制剂雷帕霉素不能有效防治DN，而我们预实验又发现抑制mTOR活性并不能有效促进TEC溶酶体生源的前提下，筛选非mTOR依赖、可联合调控TFEB/ZKSCAN3平衡进而促进TEC溶酶体更新并疏通自噬通路的上游靶点。

Our previous studies found that the depletion of lysosomal function and the blockage of autophagy pathway in renal tubular epithelial cell (TEC) of patients with diabetes mellitus (DM) would lead to TEC injury. Therefore, promoting lysosomal regeneration and dredging autophagy pathway in TEC are of great significance to delay the progress of diabetic nephropathy, but there is no effective intervention at present. After having confirmed that insufficient lysosomal biogenesis in diabetic TEC was associated with decreased expression of TFEB which promotes autophagy and lysosomal-associated gene transcription and increased expression of ZKSCAN3 which inhibits transcription of these genes in our preliminary experiments, we postulated that these two transcription factors synergistically perform autophagy and lysosomal biogenesis and functional regulation in the opposite direction. In this study, we will first verify that the imbalance of autophagy and lysosome-related genes transcriptional co-regulation caused by TFEB/ZKSCAN3 imbalance may be an important mechanism leading to the lysosome biogenesis insufficient, regeneration impairment and TEC damage in the state of DM. Furthermore, screen for non-mTOR-dependent upstream intervention targets which can jointly regulate TFEB/ZKSCAN3 balance, promoting lysosomal regeneration and unblock autophagy pathway in TEC under the premise that mTOR inhibitors couldn’t effectively prevent and treat diabetic nephropathy and our preliminary experiments showed that inhibiting mTOR did not effectively promote lysosomal biogenesis.