Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism
Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism
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DOI：
10.1002/advs.202306365
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发表时间：
2023-12
期刊：
影响因子：
15.1
通讯作者：
Hua Qu;Xiufei Liu;Jiaran Zhu;Xin Xiong;Lu Li;Qingshan He;Yuren Wang;Guojun Yang;
中科院分区：
文献类型：
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作者：
Hua Qu;Xiufei Liu;Jiaran Zhu;Xin Xiong;Lu Li;Qingshan He;Yuren Wang;Guojun Yang;
足细胞对脂质积聚特别敏感，脂质积聚最近已成为蛋白尿肾病如糖尿病肾病和局灶节段性肾小球硬化症进展中的关键病理过程。然而，其潜在机制仍不清楚。在此，足细胞主要表达的胞质分裂专用蛋白5（Dock 5）被筛选为与足细胞脂质脂毒性密切相关。其表达在蛋白尿肾病患者和小鼠模型中均降低。Dock 5的足细胞特异性缺陷加剧了蛋白尿肾病中的足细胞损伤和肾小球病理，这主要是通过调节肝脏X受体α（LXRα）/清道夫受体B类（CD 36）信号通路的脂肪酸摄取。具体而言，Dock 5缺陷通过以m6 A依赖性方式上调LXRα来增强CD 36介导的足细胞脂肪酸摄取。此外，Dock 5表达的拯救改善了足细胞损伤和蛋白尿肾病。因此，研究结果表明，Dock 5缺陷是足细胞脂毒性的关键因素，并可能成为蛋白尿肾病的一个有前途的治疗靶点。
Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.