Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan.
Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 62247, Taiwan.
Cells. 2024 Oct 14;13(20):1701. doi: 10.3390/cells13201701.
The epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of kidney fibrosis, and kidney fibrosis is associated with an adverse renal prognosis. Beta-mangostin (β-Mag) is a xanthone derivative obtained from mangosteens that is involved in the generation of antifibrotic and anti-oxidation effects. The purpose of this study was to examine the effects of β-Mag on renal tubulointerstitial fibrosis both in vivo and in vitro and the corresponding mechanisms involved. As shown through an in vivo study conducted on a unilateral ureteral obstruction mouse model, oral β-Mag administration, in a dose-dependent manner, caused a lesser degree of tubulointerstitial damage, diminished collagen I fiber deposition, and the depressed expression of fibrotic markers (collagen I, α-SMA) and EMT markers (N-cadherin, Vimentin, Snail, and Slug) in the UUO kidney tissues. The in vitro part of this research revealed that β-Mag, when co-treated with transforming growth factor-β1 (TGF-β1), decreased cell motility and downregulated the EMT (in relation to Vimentin, Snail, and N-cadherin) and phosphoryl-JNK1/2/Smad2/Smad3 expression. Furthermore, β-Mag co-treated with SB (Smad2/3 kinase inhibitor) or SP600125 (JNK kinase inhibitor) significantly inhibited the TGF-β1-associated downstream phosphorylation and activation of JNK1/2-mediated Smad2 targeting the Snail/Vimentin axis. To conclude, β-Mag protects against EMT and kidney fibrotic processes by mediating the TGF-β1/JNK/Smad2 targeting Snail-mediated Vimentin expression and may have therapeutic implications for renal tubulointerstitial fibrosis.
上皮间质转化（EMT）在肾纤维化发病机制中起关键作用，而肾纤维化与不良的肾脏预后有关。β-倒捻子素（β-Mag）是一种从山竹果中提取的呫吨酮衍生物，参与产生抗纤维化和抗氧化作用。本研究旨在探讨β-Mag 在体内和体外对肾小管间质纤维化的影响及其相关机制。在单侧输尿管梗阻（UUO）小鼠模型的体内研究中，β-Mag 以剂量依赖性方式口服给药，导致肾小管间质损伤程度较轻，胶原 I 纤维沉积减少，纤维化标志物（胶原 I、α-SMA）和 EMT 标志物（N-钙粘蛋白、波形蛋白、Snail 和 Slug）在 UUO 肾脏组织中的表达下调。本研究的体外部分表明，β-Mag 与转化生长因子-β1（TGF-β1）共同处理时，降低了细胞迁移能力，并下调了 EMT（与波形蛋白、Snail 和 N-钙粘蛋白有关）和磷酸化-JNK1/2/Smad2/Smad3 表达。此外，β-Mag 与 SB（Smad2/3 激酶抑制剂）或 SP600125（JNK 激酶抑制剂）共同处理时，显著抑制 TGF-β1 相关下游磷酸化和 JNK1/2 介导的 Smad2 对 Snail/Vimentin 轴的靶向作用。总之，β-Mag 通过介导 TGF-β1/JNK/Smad2 靶向 Snail 介导的波形蛋白表达来保护 EMT 和肾纤维化过程，可能对肾小管间质纤维化具有治疗意义。
