Notch1 regulates PTEN expression to exacerbate renal tubulointerstitial fibrosis in diabetic nephropathy by inhibiting autophagy via interactions with Hes1
Notch1 regulates PTEN expression to exacerbate renal tubulointerstitial fibrosis in diabetic nephropathy by inhibiting autophagy via interactions with Hes1
复制标题
Notch1 通过与 Hes1 相互作用抑制自噬来调节 PTEN 表达，从而加剧糖尿病肾病的肾小管间质纤维化。
DOI：
10.1016/j.bbrc.2018.02.187
复制
发表时间：
2018-03-18
影响因子：
3.1
通讯作者：
Guo, Bing
中科院分区：
文献类型：
--
作者：
Liu, XingMei;Zhang, YingYing;Guo, Bing
糖尿病肾病（DN）是糖尿病严重的临床微血管并发症。DN的特征在于细胞外基质的积聚，导致进行性纤维化，从而导致肾功能丧失。Notch1和10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）信号传导与纤维化相关。自噬是肾小管细胞内环境稳定的重要调节因子。然而，这些分子如何控制纤维化和自噬之间的平衡，调节纤维化的主要稳态机制，还没有得到很好的理解。使用Notchl-siRNA在体外证实了这种关联，其阻止了Hes1的增加并恢复了PTEN表达。与此相反，转染pHAGE-Hest抑制PTEN启动子驱动的荧光素酶活性，这意味着Hes1和PTEN之间的直接关系。Western blotting结果显示糖尿病db/db小鼠Notch1和Hes1表达增加，而PTEN表达减少。重要的是，这些信号分子的失调与细胞外基质蛋白（胶原蛋白-I和III）的增加和自噬的抑制有关。类似的结果在NRK-52e细胞中对体外高葡萄糖浓度的响应中是明显的。因此，糖尿病中存在的高葡萄糖浓度通过Notch1途径经由Hest促进纤维化，同时抑制PTEN和自噬。总之，Notch1/Hes1对PTEN的抑制响应于高葡萄糖浓度抑制了自噬，这与纤维化的进展有关。因此，这些信号分子可能代表糖尿病肾病的新的治疗靶点。(C)2018爱思唯尔公司All rights reserved.
Diabetic nephropathy (DN) is a serious clinical microvascular complication of diabetes mellitus. DN is characterized by the accumulation of extracellular matrix, resulting in progressive fibrosis leading to the loss of renal function. Notch1 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling have been associated with fibrosis. Autophagy serves as an essential regulator of tubular cellular homeostasis. However, how these molecules control the balance between fibrosis and autophagy, the main homeostatic mechanism regulating fibrosis, is not well understood. This association was confirmed using Notchl-siRNA in vitro, which prevented the increase in Hes1 and restored PTEN expression. In contrast, transfection with pHAGE-Hest repressed PTEN promoter-driven luciferase activity, implying a direct relationship between Hes1 and PTEN. The expression of Notch1 and Hes1 was increased in diabetic db/db mice by western blotting; in contrast, the expression of PTEN was decreased. Importantly, the dysregulation of these signaling molecules was associated with an increase in extra cellular matrix proteins (Collagen-I and III) and the inhibition of autophagy. Similar results were evident in response to high glucose concentrations in vitro in the NRK-52e cells. Therefore, the high glucose concentrations present in diabetes promote fibrosis through the Notch1 pathway via Hest, while inhibiting the PTEN and autophagy. In conclusion, the inhibition of PTEN by Notch1/Hes1 in response to high glucose concentration inhibits autophagy, which is associated with the progression of fibrosis. Therefore, these signaling molecules may represent novel therapeutic targets in diabetic nephropathy. (C) 2018 Elsevier Inc. All rights reserved.