Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation
Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation
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DOI：
10.1038/s41401-022-00997-1
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发表时间：
2022-11-08
影响因子：
8.2
通讯作者：
Wang，Yuan-yuan
中科院分区：
文献类型：
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作者：
Zhang，Hui-fang;Liu，Hui-ming;Wang，Yuan-yuan
以往的研究表明，线粒体功能障碍在各种急性肾损伤和慢性肾脏疾病。在受损器官中，硫辛酸对氧化应激和线粒体功能的调节具有强有力的作用。在这项研究中，我们调查是否α硫辛酰胺（ALM），硫辛酸的衍生物，在2型糖尿病小鼠模型中发挥肾脏保护作用。9周龄ddb/db小鼠用ALM（50 mg·kg-1·d-1，i.g）处理8周。我们发现，ALM给药不影响indb/db小鼠的血糖水平，但恢复了肾功能并显著改善了肾脏纤维化。我们证明，ALM给药显著改善db/db小鼠肾脏中的线粒体功能障碍和肾小管间质纤维化病变，沿着CDX 2和CFTR表达增加以及β-连环蛋白和Snail表达减少。在高糖培养基中培养的大鼠肾小管上皮细胞系NRK-52 E中，用ALM（200 μM）处理后观察到类似的保护作用。进一步探讨了ALM对糖尿病肾病（DKD）的保护机制：Autodock维纳软件预测ALM可通过形成稳定的氢键激活RXRα蛋白。PROMO数据库预测RXRα可与CDX 2基因启动子序列结合。在正常葡萄糖条件下，NRK-52 E细胞中RXRα表达的敲低抑制了CDX 2的表达，并促进了肾小管上皮细胞的表型改变。然而，RXRα过表达增加了CDX 2的表达，这反过来又抑制了高糖介导的肾小管上皮细胞损伤。因此，我们揭示了ALM对DKD的保护作用及其可能的潜在靶点：ALM通过上调和激活RXRα改善线粒体功能障碍并调节CDX 2/CFTR/β-catenin信号传导轴。示意图说明ALM通过改善线粒体功能和上调和激活RXRα来减轻糖尿病肾病，其反过来上调CDX 2以对β-catenin活化和核转位发挥抑制作用。肾小管上皮细胞。ROS活性氧RXRα维甲酸X受体-α。Mfn1 Mitofusin 1. drp 1动力相关蛋白1。MDA丙二醛。4-HNE 4-羟基壬烯醛T-SOD总超氧化物歧化酶CDX 2尾型同源框转录因子2。囊性纤维化跨膜传导调节因子。EMT上皮间质转化。α-平滑肌肌动蛋白。ECM细胞外基质。DKD糖尿病肾病。示意图由Figdraw（www.figdraw.com）绘制。
Previous studies have shown mitochondrial dysfunction in various acute kidney injuries and chronic kidney diseases. Lipoic acid exerts potent effects on oxidant stress and modulation of mitochondrial function in damaged organ. In this study we investigated whether alpha lipoamide (ALM), a derivative of lipoic acid, exerted a renal protective effect in a type 2 diabetes mellitus mouse model. 9-week-olddb/dbmice were treated with ALM (50 mg·kg−1·d−1, i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels indb/dbmice, but restored renal function and significantly improved fibrosis of kidneys. We demonstrated that ALM administration significantly ameliorated mitochondrial dysfunction and tubulointerstitial fibrotic lesions, along with increased expression of CDX2 and CFTR and decreased expression of β-catenin and Snail in kidneys ofdb/dbmice. Similar protective effects were observed in rat renal tubular epithelial cell line NRK-52E cultured in high-glucose medium following treatment with ALM (200 μM). The protective mechanisms of ALM in diabetic kidney disease (DKD) were further explored: Autodock Vina software predicted that ALM could activate RXRα protein by forming stable hydrogen bonds. PROMO Database predicted that RXRα could bind the promoter sequences ofCDX2gene. Knockdown of RXRα expression in NRK-52E cells under normal glucose condition suppressed CDX2 expression and promoted phenotypic changes in renal tubular epithelial cells. However, RXRα overexpression increased CDX2 expression which in turn inhibited high glucose-mediated renal tubular epithelial cell injury. Therefore, we reveal the protective effect of ALM on DKD and its possible potential targets: ALM ameliorates mitochondrial dysfunction and regulates the CDX2/CFTR/β-catenin signaling axis through upregulation and activation of RXRα.Schematic figure illustrating that ALM alleviates diabetic kidney disease by improving mitochondrial function and upregulation and activation of RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on β-catenin activation and nuclear translocation. RTEC renal tubular epithelial cell. ROS Reactive oxygen species. RXRα Retinoid X receptor-α. Mfn1 Mitofusin 1. Drp1 dynamic-related protein 1. MDA malondialdehyde. 4-HNE 4-hydroxynonenal. T-SOD Total-superoxide dismutase. CDX2 Caudal-type homeobox transcription factor 2. CFTR Cystic fibrosis transmembrane conductance regulator. EMT epithelial mesenchymal transition. α-SMA Alpha-smooth muscle actin. ECM extracellular matrix. DKD diabetic kidney disease. Schematic figure was drawn by Figdraw (www.figdraw.com).