State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550025, China.
International Scientific and Technological Cooperation Base of Pathogenesis and Drug Research on Common Major Diseases, Guizhou Medical University, Guiyang, 550025, China.
Acta Pharmacol Sin. 2023 May;44(5):1051-1065. doi: 10.1038/s41401-022-00997-1. Epub 2022 Nov 8.
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-old db/db mice were treated with ALM (50 mg·kg·d, i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels in db/db mice, 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 of db/db mice. 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 of CDX2 gene. 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 ).
先前的研究表明，线粒体功能障碍存在于各种急性肾损伤和慢性肾脏病中。硫辛酸对氧化应激和受损器官中线粒体功能的调节有很强的作用。在这项研究中，我们研究了 2 型糖尿病小鼠模型中，α-硫辛酸（ALM），一种硫辛酸的衍生物，是否具有肾脏保护作用。9 周龄的 db/db 小鼠用 ALM（50mg·kg·d，ig）治疗 8 周。我们发现，ALM 给药不会影响 db/db 小鼠的血糖水平，但恢复了肾功能，并显著改善了肾脏的纤维化。我们证明，ALM 给药可显著改善线粒体功能障碍和肾小管间质纤维化病变，同时增加 db/db 小鼠肾脏中 CDX2 和 CFTR 的表达，降低β-连环蛋白和 SNAIL 的表达。在高糖培养基中培养的大鼠肾小管上皮细胞系 NRK-52E 中，给予 ALM（200μM）也观察到类似的保护作用。进一步探讨了 ALM 在糖尿病肾病（DKD）中的保护机制：Autodock Vina 软件预测，ALM 可以通过形成稳定的氢键来激活 RXRα 蛋白。PROMO 数据库预测，RXRα 可以结合 CDX2 基因的启动子序列。在正常葡萄糖条件下，NRK-52E 细胞中 RXRα 表达的敲低抑制了 CDX2 的表达，并促进了肾小管上皮细胞的表型变化。然而，RXRα 的过表达增加了 CDX2 的表达，从而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，并调节 CDX2/CFTR/β-连环蛋白信号通路。示意图说明了 ALM 通过改善线粒体功能和上调及激活 RXRα 来减轻糖尿病肾病，从而上调 CDX2，对β-连环蛋白的激活和核转位产生抑制作用。RTEC 肾小管上皮细胞。ROS 活性氧。RXRα 视黄酸受体-α。Mfn1 线粒体融合蛋白 1。Drp1 动力相关蛋白 1。MDA 丙二醛。4-HNE 4-羟壬烯醛。T-SOD 总超氧化物歧化酶。CDX2 尾型同源盒转录因子 2。CFTR 囊性纤维化跨膜电导调节体。EMT 上皮间质转化。α-SMA 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。
