Magnesium isoglycyrrhizinate ameliorates fructose-induced podocyte apoptosis through downregulation of miR-193a to increase WT1
Magnesium isoglycyrrhizinate ameliorates fructose-induced podocyte apoptosis through downregulation of miR-193a to increase WT1
复制标题
异甘草酸镁通过下调 miR-193a 增加 WT1 改善果糖诱导的足细胞凋亡
DOI：
10.1016/j.bcp.2019.05.016
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发表时间：
2019-08-01
影响因子：
5.8
通讯作者：
Kong, Ling-Dong
中科院分区：
文献类型：
--
作者：
Li, Tu-Shuai;Chen, Li;Kong, Ling-Dong
高果糖摄入量是肾小球足细胞功能障碍的风险。足细胞凋亡已成为足细胞丢失的主要原因，加剧了蛋白尿。异甘草酸镁(MIG)是临床上常用的肝脏保护剂。肝肾损伤是人类疾病中的常见病。最近的报道表明，镁球蛋白可以改善肾功能。在这项研究中，我们发现镁免疫球蛋白显著减轻果糖喂养大鼠的肾功能障碍、蛋白尿和足细胞损伤。它还能恢复果糖诱导的大鼠肾小球和培养分化的足细胞的凋亡。值得注意的是，在这些动物和细胞模型中观察到miR-193a的高表达，Wilms肿瘤蛋白(WT1)和relA的下调，以及C-Maf诱导蛋白(C-MIP)的上调。将miR-193a模拟物、miR-193a抑制剂、WT1 siRNA或LV5-WT1分别导入分化后的足细胞，结果显示果糖可上调miR-193a下调WT1，进而激活C-MIP抑制RelA，导致足细胞凋亡。这些干扰被镁免疫球蛋白显著减弱。综上所述，这些结果首次证明，镁免疫球蛋白至少部分地通过抑制miR-193a上调WT1来抑制果糖诱导的足细胞凋亡，支持了镁免疫球蛋白的应用，其具有一种新的作用机制，即对抗与果糖诱导的肾功能障碍相关的足细胞凋亡。
High fructose intake is a risk of glomerular podocyte dysfunction. Podocyte apoptosis has emerged as a major cause of podocyte loss, exacerbating proteinuria. Magnesium isoglycyrrhizinate (MgIG) is usually used as a hepatoprotective agent in clinic. Liver and kidney injury often occurs in human diseases. Recent report shows that MgIG improves kidney function. In this study, we found that MgIG significantly alleviated kidney dysfunction, proteinuria and podocyte injury in fructose-fed rats. It also restored fructose-induced podocyte apoptosis in rat glomeruli and cultured differentiated podocytes. Of note, high-expression of miR-193a, down-regulation of Wilms' tumor protein (WT1) and RelA, as well as upregulation of C-Maf inducing protein (C-mip) were observed in these animal and cell models. The data from the transfection of miR-193a mimic, miR-193a inhibitor, WT1 siRNA or LV5-WT1 in cultured differentiated podocytes showed that fructose increased miR-193a to down-regulate WT1, and subsequently activated C-mip to suppress RelA, causing podocyte apoptosis. These disturbances were significantly attenuated by MgIG. Taken together, these results provide the first evidence that MgIG restrains fructose-induced podocyte apoptosis at least partly through inhibiting miR-193a to upregulate WT1, supporting the application of MgIG with a novel mechanism-of-action against podocyte apoptosis associated with fructose-induced kidney dysfunction.