Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213000, Jiangsu Province, People's Republic of China.
Department of Pediatrics, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213000, Jiangsu Province, People's Republic of China.
Biochem Biophys Res Commun. 2022 Aug 27;618:38-45. doi: 10.1016/j.bbrc.2022.06.019. Epub 2022 Jun 9.
Podocyte injury is the main clinical pathological feature of diabetic kidney disease (DKD). The studies showed that DKD is associated with the polarization of macrophages to different types (M1 or M2) and the inflammatory processes which they mediate. It is a hot research topic in the treatment of DKD that find and intervene genes which related to M1/M2 phenotype. The potential anti-inflammatory effects on γ-aminobutyric acid (GABA) have been shown to be related to the regulation of the polarization direction of macrophages. However, it remains unknown that whether GABA can alleviate DKD. The purpose of current study was to explore the role of GABA involved in high glucose (HG)-induced podocyte injury by regulating the M1/M2 phenotype. In the beginning, our results revealed that exogenous GABA treatment altered the direction of HG-induced macrophage polarization and suppressed the inflammatory response. Subsequently, macrophage-derived exosomes under HG treatment were found to be involved in aggravating HG-induced podocyte injury (decreased the proliferation capacity and increased apoptosis rate of cells). Furthermore, GABA treatment blocked the promotion of macrophage-mediated exosomes on podocyte injury under HG. Then, we found that GABA alleviated the promoting effect of macrophages on podocyte injury by regulating the expression of exosomal miR-21a-5p/miR-25-3p which mediated by macrophages. Finally, it was elucidated that Tnpo1/ATXN3 were the targets of miR-21a-5p/miR-25-3p, respectively, and mediated the promotion of podocyte injury by macrophage-derived exosomes under HG. This research suggested that GABA alleviated podocyte injury by reversing the M1/M2 polarization direction of macrophages under HG and regulating the miR-21a-5p-Tnpo1/miR-25-3p-ATXN3 signal axis of macrophage-derived exosomes.
足细胞损伤是糖尿病肾病 (DKD) 的主要临床病理特征。研究表明，DKD 与巨噬细胞向不同类型（M1 或 M2）极化以及它们介导的炎症过程有关。寻找和干预与 M1/M2 表型相关的基因是治疗 DKD 的一个热门研究课题。γ-氨基丁酸 (GABA) 的潜在抗炎作用与调节巨噬细胞极化方向有关。然而，目前尚不清楚 GABA 是否可以缓解 DKD。本研究旨在通过调节 M1/M2 表型，探讨 GABA 参与高糖 (HG) 诱导的足细胞损伤的作用。首先，我们的结果表明，外源性 GABA 处理改变了 HG 诱导的巨噬细胞极化方向，并抑制了炎症反应。随后，发现 HG 处理下的巨噬细胞衍生的外体参与加重 HG 诱导的足细胞损伤（降低细胞的增殖能力并增加细胞凋亡率）。此外，GABA 处理阻断了 HG 下巨噬细胞介导的外体对足细胞损伤的促进作用。然后，我们发现 GABA 通过调节巨噬细胞表达的外泌体 miR-21a-5p/miR-25-3p 来减轻巨噬细胞对足细胞损伤的促进作用。最后，阐明 Tnpo1/ATXN3 分别是 miR-21a-5p/miR-25-3p 的靶基因，并介导 HG 下巨噬细胞衍生的外体对足细胞损伤的促进作用。这项研究表明，GABA 通过逆转 HG 下巨噬细胞的 M1/M2 极化方向并调节巨噬细胞衍生的外体的 miR-21a-5p-Tnpo1/miR-25-3p-ATXN3 信号轴来减轻足细胞损伤。
