Figure 4.

Proposed EV pathways in the pathogenesis of renal fibrosis. EVs are produced in enhanced numbers by stressed or injured TEC downstream of Shh and they cause proliferation and fibrogenesis in fibroblasts, in part by downregulation of SOCS2 by EV miR-196b-5p. TEC EVs also drive EMT and activation in TEC themselves via processes that are dependent on the action of EV TGF-β, transglutaminase 2, or miR-21, the latter of which is associated with regulation of PTEN/AKT or PPAR/HIF in recipient cells. Podocyte injury and drop-out is a feature of DN and EVs from these cells are present in urine and, when produced in the context of DN-like high glucose conditions, drive ECM production via a TGF-β/p38/Smad axis in TEC and mesangial cells. High glucose levels also result in the production of EVs by GEC that drive Wnt/β-catenin-mediated EMT in podocytes or circular RNA-mediated EMT in mesangial cells. Macrophages exposed to high glucose produce pro-inflammatory EVs that are themselves macrophage-activating and further stimulate TGF-β-dependent activation of mesangial cells. Production by mesangial cells of pro-fibrogenic and pro-pathogenic molecules such as FN and Ang II is stimulated by EVs that are produced by mesangial cells exposed to high glucose concentrations. Only cells with a demonstrated role in EV production or response are shown; some of the depicted EV pathways are deduced from in vitro observations and have not been demonstrated in vivo. See text for details.