Extracellular Vesicles from Albumin-Induced Tubular Epithelial Cells Promote the M1 Macrophage Phenotype by Targeting Klotho
Extracellular Vesicles from Albumin-Induced Tubular Epithelial Cells Promote the M1 Macrophage Phenotype by Targeting Klotho
复制标题
白蛋白诱导的管状上皮细胞的细胞外囊泡通过靶向 Klotho 促进 M1 巨噬细胞表型
DOI：
10.1016/j.ymthe.2019.05.019
复制
发表时间：
2019-08-07
影响因子：
12.4
通讯作者：
Xue, Yaoming
中科院分区：
文献类型：
--
作者：
Jia, Yijie;Zheng, Zongji;Xue, Yaoming
白蛋白被肾小管上皮细胞吸收诱导炎症，在促进糖尿病肾病(DKD)进展中起关键作用。巨噬细胞是肾脏中重要的炎性细胞，它们在肾脏中的作用取决于它们的表型。然而，在DKD的发生发展过程中，蛋白尿是否影响巨噬细胞的表型和潜在的机制仍不清楚。我们发现随着DKD的发展，糖尿病(DM)小鼠肾组织中M1巨噬细胞相关标志物的表达增加，人血清白蛋白(HSA)诱导的HK-2细胞胞外小泡(EV)与巨噬细胞共培养后，在脂多糖(LPS)存在下，巨噬细胞M1极化。通过生物信息学分析，筛选出miR-199a-5p，发现miR-199a-5p在HSA诱导的HK-2细胞的EVS和糖尿病伴大量白蛋白尿患者的尿EVS中表达增加。尾静脉注射HSA诱导的HK-2细胞的EV可通过miR-199a-5p促进糖尿病小鼠肾脏巨噬细胞M1极化，加速DKD的进展。MIR-199a-5p通过靶向Klotho发挥作用，Klotho在体内和体外均通过Toll样受体4(TLR4)途径诱导巨噬细胞M2极化。综上所述，HSA刺激的HK-2细胞来源的EVS中的miR-199a-5p通过靶向Klotho/TLR4途径诱导M1极化，进一步加速DKD的进展。
Albumin absorbed by renal tubular epithelial cells induces inflammation and plays a key role in promoting diabetic kidney disease (DKD) progression. Macrophages are prominent inflammatory cells in the kidney, and their role there is dependent on their phenotypes. However, whether albuminuria influences macrophage phenotypes and underlying mechanisms during the development of DKD is still unclear. We found that M1 macrophage-related markers were increased in diabetes mellitus (DM) mouse renal tissues with the development of DKD, and coculture of extracellular vesicles (EVs) from human serum albumin (HSA)-induced HK-2 cells with macrophages induced macrophage M1 polarization in the presence of lipopolysaccharide (LPS). Through a bioinformatic analysis, miR-199a-5p was selected and found to be increased in EVs from HSA-induced HK-2 cells and in urinary EVs from DM patients with macroalbuminuria. Tail-vein injection of DM mice with EVs from HSA-induced HK-2 cells induced kidney macrophage M1 polarization and accelerated the progression of DKD through miR-199a-5p. miR-199a-5p exerted its effect by targeting Klotho, and Klotho induced macrophage M2 polarization through the Toll-like receptor 4 (TLR4) pathway both in vivo and in vitro. In summary, miR-199a-5p from HSA-stimulated HK-2 cell-derived EVs induces M1 polarization by targeting the Klotho/TLR4 pathway and further accelerates the progression of DKD.