GABA alleviates high glucose-induced podocyte injury through dynamically altering the expression of macrophage M1/M2-derived exosomal miR-21a-5p/miR-25-3p

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.