黄芪甲苷通过 CX3CL1-RAF/MEK/ERK 信号通路减轻糖尿病肾病肾小管上皮间质转化。
Astragaloside IV Alleviates Renal Tubular Epithelial-Mesenchymal Transition via CX3CL1-RAF/MEK/ERK Signaling Pathway in Diabetic Kidney Disease.
机构信息
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People's Republic of China.
Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, People's Republic of China.
出版信息
Drug Des Devel Ther. 2022 May 31;16:1605-1620. doi: 10.2147/DDDT.S360346. eCollection 2022.
BACKGROUND
Epithelial-mesenchymal transition (EMT) plays an important role in interstitial matrix deposition and renal fibrosis in diabetic kidney disease (DKD). It has been verified that Astragaloside IV (AS-IV) is beneficial for ameliorating DKD. However, the underlying mechanisms of AS-IV on regulating EMT in DKD are yet to be established. Accumulated evidence has suggested that C-X3-C motif ligand 1 (CX3CL1) plays a significant role in the progression of EMT.
PURPOSE
We aimed to investigate whether AS-IV could alleviate EMT by regulating CX3CL1 in DKD and reveal its underlying mechanisms.
METHODS
For the in vivo study, mice were divided into the following five groups (n=10): db/m+vehicle, db/db+vehicle, db/db+AS-IV-L (10mg/kg/d), db/db+AS-IV-M (20mg/kg/d), db/db+AS-IV-H (40mg/kg/d). After 12 weeks of treatment, the renal injuries were assessed based on the related parameters of urine, blood and histopathological examination. Immunohistochemistry and Western blotting were used to detect relative proteins levels. Then in HK-2 cells, the molecular mechanism of AS-IV attenuating the EMT in mice with DKD through the CX3CL1-RAF/MEK/ERK pathway was studied.
RESULTS
In the present study, we found that AS-IV reduced urinary protein levels and improved renal pathological damage in DKD mice. Moreover, AS-IV ameliorated the renal tubular EMT induced by hyperglycemia or high glucose (HG), and decreased the expression of CX3CL1 and inhibited the activation of the RAF/MEK/ERK pathway in vivo and in vitro. In HK-2 cells, downregulation of CX3CL1 suppressed the stimulation of the RAF/MEK/ERK pathway and EMT induced by HG. However, CX3CL1 overexpression eliminated the benefits of AS-IV on the RAF/MEK/ERK pathway and EMT.
CONCLUSION
In summary, we indicated that AS-IV alleviates renal tubular EMT through the CX3CL1-RAF/MEK/ERK signaling pathway, indicating that CX3CL1 could be a potential therapeutic target of AS-IV in DKD.
背景
上皮-间充质转化（EMT）在糖尿病肾病（DKD）的间质基质沉积和肾纤维化中起重要作用。已经验证黄芪甲苷（AS-IV）有利于改善 DKD。然而，AS-IV 调节 DKD 中 EMT 的潜在机制尚待确定。越来越多的证据表明，C-X3-C 趋化因子配体 1（CX3CL1）在 EMT 的进展中起着重要作用。
目的
本研究旨在探讨 AS-IV 是否可以通过调节 DKD 中的 CX3CL1 来减轻 EMT，并揭示其潜在机制。
方法
在体内研究中，将小鼠分为以下五组（每组 n=10）：db/m+载体，db/db+载体，db/db+AS-IV-L（10mg/kg/d），db/db+AS-IV-M（20mg/kg/d），db/db+AS-IV-H（40mg/kg/d）。治疗 12 周后，根据尿液、血液和组织病理学检查的相关参数评估肾脏损伤。免疫组织化学和 Western blot 用于检测相对蛋白水平。然后，在 HK-2 细胞中，研究了 AS-IV 通过 CX3CL1-RAF/MEK/ERK 通路减轻 DKD 小鼠 EMT 的分子机制。
结果
本研究发现，AS-IV 降低了 DKD 小鼠的尿蛋白水平并改善了肾脏病理损伤。此外，AS-IV 改善了高糖或高葡萄糖（HG）诱导的肾小管 EMT，并降低了体内和体外 CX3CL1 的表达并抑制了 RAF/MEK/ERK 通路的激活。在 HK-2 细胞中，下调 CX3CL1 抑制了 HG 刺激的 RAF/MEK/ERK 通路和 EMT。然而，CX3CL1 的过表达消除了 AS-IV 对 RAF/MEK/ERK 通路和 EMT 的益处。
结论
总之，我们表明 AS-IV 通过 CX3CL1-RAF/MEK/ERK 信号通路减轻肾小管 EMT，表明 CX3CL1 可能是 AS-IV 在 DKD 中的潜在治疗靶点。
Zotero 插件