Chen Lin, Chen Dan-Qian, Wang Ming, Liu Dan, Chen Hua, Dou Fang, Vaziri Nosratola D, Zhao Ying-Yong
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA 92897, USA.
Chem Biol Interact. 2017 Aug 1;273:56-72. doi: 10.1016/j.cbi.2017.05.025. Epub 2017 Jun 2.
Renin-angiotensin system (RAS) plays a key role in the development and progression of chronic kidney disease (CKD). Recent studies have demonstrated activation of Wnt/β-catenin pathway by RAS in CKD. However, the underlying mechanisms of RAS and Wnt/β-catenin signaling interaction and their contribution to the pathogenesis of CKD have not been fully elucidated. Present study is designed to investigate the role of RAS/Wnt/β-catenin axis activation in tubulo-interstitial fibrosis and glomerulosclerosis by the cultured HK-2 and podocytes. HK-2 cells and podocytes are treated by angiotensin II (Ang II). Ang II up-regulates expression of various Wnt mRNA and active β-catenin protein in HK-2 cells and podocytes in the time- and dose-dependent manners. In addition, Ang II induces injury, oxidative stress and inflammation and impaired Nrf2 activation in HK-2 cells and podocytes. This was accompanied by up-regulations of RAS components as well as Wnt1, activated β-catenin and its target proteins. RAS/Wnt/β-catenin axis activation results in epithelial-to-mesenchymal transition in HK-2 cells and injuries podocytes. The effect of Ang II is inhibited by losartan and ICG-001, a Wnt/β-catenin inhibitor. We further found that treatment with natural products, ergone, alisol B 23-acetate and pachymic acid B inhibit extracellular matrix accumulation in HK-2 cells and attenuated podocyte injury, in part, by inhibiting Ang II induced RAS/Wnt/β-catenin axis activation. In summary, activation of RAS/Wnt/β-catenin axis results in podocytes and tubular epithelial cell, injury and up-regulations of oxidative, inflammatory and fibrotic pathways. These adverse effects are ameliorated by ergone, alisol B 23-acetate and pachymic acid B. Therefore, these natural products could be considered as novel Wnt/β-catenin signaling inhibitors and anti-fibrotic agents.
肾素-血管紧张素系统（RAS）在慢性肾脏病（CKD）的发生和发展中起关键作用。最近的研究表明，RAS可激活CKD中的Wnt/β-连环蛋白信号通路。然而，RAS与Wnt/β-连环蛋白信号相互作用的潜在机制及其对CKD发病机制的作用尚未完全阐明。本研究旨在通过培养的HK-2细胞和足细胞，研究RAS/Wnt/β-连环蛋白轴激活在肾小管间质纤维化和肾小球硬化中的作用。用血管紧张素II（Ang II）处理HK-2细胞和足细胞。Ang II以时间和剂量依赖性方式上调HK-2细胞和足细胞中各种Wnt mRNA和活性β-连环蛋白的表达。此外，Ang II诱导HK-2细胞和足细胞损伤、氧化应激和炎症，并损害Nrf2激活。这伴随着RAS成分以及Wnt1、活化的β-连环蛋白及其靶蛋白的上调。RAS/Wnt/β-连环蛋白轴激活导致HK-2细胞上皮-间质转化和足细胞损伤。氯沙坦和Wnt/β-连环蛋白抑制剂ICG-001可抑制Ang II的作用。我们进一步发现，天然产物麦角硫因、泽泻醇B 23-乙酸酯和茯苓酸B处理可抑制HK-2细胞外基质积聚，并部分减轻足细胞损伤，其机制可能是抑制Ang II诱导的RAS/Wnt/β-连环蛋白轴激活。总之，RAS/Wnt/β-连环蛋白轴激活导致足细胞和肾小管上皮细胞损伤，并上调氧化、炎症和纤维化通路。麦角硫因、泽泻醇B 23-乙酸酯和茯苓酸B可改善这些不良反应。因此，这些天然产物可被视为新型Wnt/β-连环蛋白信号抑制剂和抗纤维化药物。
