Fig. 3.

Pathways of ADAM17 in the regulation of tubular epithelial cells, mesangial cells and podocytes. In response to kidney injury, ADAM17 activates the epidermal growth factor receptor pathway by inducing the MEK/ERK signaling, the JAK/STAT signaling and the NFκB signaling, which induces proinflammatory factors upregulation, inflammatory cell infiltration, and profibrotic factors release. The increased ADAM17-mediated ACE2 shedding exacerbates the imbalance of RAS, which increases inflammation and fibrosis in a looping feedback manner. And ADAM17 is involved in shedding membrane-bound IL-6 receptor and activating the IL-6 trans-signaling, which mediates renal inflammation and fibrosis by inducing the MAPK/ERK signaling, the JAK/STAT signaling, and the PI3K/AKT1 signaling. Moreover, ADAM17 mediates the release of CXCL16, which induces T cells and macrophages infiltration. In addition, the shedding of NADPH oxidase 4 (Nox4) mediating ROS upregulation and matrix accumulation known to be implicated by ADAM17.