Li Xin, Fan Qiu-Ling, Ma Tian-Kui, Liu Cong, Shi Hang, Sun Yuan-Yuan, Wang Yue, Ding Dong-Xue, Tang Ao, Qin Yu, Yang Qi, Ding Hong, Li Hang-Yu, Fu Wei-Neng
Department of Medical Genetics, China Medical University, Shenyang, China.
Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China.
iScience. 2023 Aug 12;26(9):107609. doi: 10.1016/j.isci.2023.107609. eCollection 2023 Sep 15.
Tubulointerstitial abnormalities contribute to the progression of diabetic kidney disease (DKD). However, the underlying mechanism of the pathobiology of tubulointerstitial disease is largely unknown. Here, we showed that MYCT1 expression was downregulated in and DKD models. Adeno-associated virus (AAV)-Myct1 significantly attenuated renal dysfunction and tubulointerstitial fibrosis in diabetic db/db mice and downregulated Sp1 transcription and TGF-β1/SMAD3 pathway activation. In human proximal tubular epithelial cells, high glucose-induced high expression of SP1 and TGF-β1/SMAD3 pathway activation as well as overaccumulation of extracellular matrix (ECM) were abrogated by MYCT1 overexpression. Mechanistically, the binding of VDR to the MYCT1 promoter was predicted and confirmed using dual-luciferase reporter and ChIP analysis. VDR transcriptionally upregulates MYCT1. Our data reveal MYCT1 as a new and potential therapeutic target in treating DKD.
肾小管间质异常促进糖尿病肾病（DKD）的进展。然而，肾小管间质疾病病理生物学的潜在机制在很大程度上尚不清楚。在此，我们表明，在[具体实验对象1]和[具体实验对象2]DKD模型中，MYCT1表达下调。腺相关病毒（AAV）-Myct1显著减轻糖尿病db/db小鼠的肾功能障碍和肾小管间质纤维化，并下调Sp1转录和TGF-β1/SMAD3信号通路激活。在人近端肾小管上皮细胞中，MYCT1过表达消除了高糖诱导的SP1高表达、TGF-β1/SMAD3信号通路激活以及细胞外基质（ECM）过度积累。机制上，使用双荧光素酶报告基因和染色质免疫沉淀分析预测并证实了VDR与MYCT1启动子的结合。VDR转录上调MYCT1。我们的数据揭示MYCT1是治疗DKD的一个新的潜在治疗靶点。
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