Department of Laboratory Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524003, PR China; Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, 110001, PR China.
Department of Nephrology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, PR China.
Phytomedicine. 2024 Jul 25;130:155705. doi: 10.1016/j.phymed.2024.155705. Epub 2024 May 3.
Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain.
To investigate the functions and potential mechanisms of the senolytics DQ on DKD.
Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector.
DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD.
For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.
达沙替尼和槲皮素（DQ）的联合使用是最具研究前景的衰老细胞清除药物，用于治疗各种与年龄相关的疾病。然而，其对糖尿病肾病（DKD）的保护作用及其潜在机制尚不清楚。
研究衰老细胞清除药物 DQ 对 DKD 的作用及潜在机制。
糖尿病 db/db 小鼠给予 DQ 或过表达 PPARα 或 shPPARα 载体转染。阳性对照组给予厄贝沙坦治疗。检测肾功能和肾脏组织纤维化变化。进行单细胞 RNA 测序（scRNA-seq）分析糖尿病和对照组小鼠之间的差异转录组。采用分子对接模拟评估 DQ 与潜在因素的结合。此外，高糖（HG）条件下的肾小管上皮细胞用 DQ 孵育，并转染过表达 PPARα/siPPARα 载体或不转染。
DQ 显著改善了 DKD 小鼠的肾功能、组织病理学和纤维化变化，减轻了脂质沉积，并增加了 ATP 水平。DQ 降低了 db/db 小鼠中多种脂肪酸氧化（FAO）途径相关蛋白的表达，并上调了 PPARα。过表达 PPARα 上调了 PPARα 靶向的下游 FAO 途径相关蛋白的表达，恢复了肾功能，并抑制了体外和体内的肾纤维化。此外，分子对接和动力学模拟分析表明，DQ 通过与 PPARα 结合发挥其肾脏保护作用。PPARα 的敲低逆转了 DQ 对 FAO 途径的作用，并损害了 DQ 在 DKD 中的保护作用。
首次发现 DQ 通过与 PPARα 结合，通过促进 DKD 中的 FAO 发挥肾脏保护作用，减轻肾脏损伤。
