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. 2016 Aug 18;1(13):e87023. doi: 10.1172/jci.insight.87023

Figure 9. Mechanisms of injury-induced ADAM17-dependent sustained EGFR activation in proximal tubule cells.

Figure 9

Injury drives upregulation of ADAM17 and of its substrates, in particular pro-AREG. Increased ADAM17 activity on the cell surface leads to enhanced release of soluble AREG and TNFα, which activate their respective receptors. In a positive feedback loop, AREG-mediated EGFR activation increases ADAM17 and AREG expression. TNFα-mediated TNFR activation strengthens this feedback loop further by enhancing soluble AREG release (pathway crosstalk). Both pathways, AREG/EGFR and TNFα/TNFR, potentiate each other in inducing profibrotic and proinflammatory cytokines that drive kidney fibrosis. pro-TNFα, transmembrane pro–tumor necrosis factor α; sTNFα, soluble tumor necrosis factor α; ADAM17, a disintegrin and metalloprotease 17; EGFR, epidermal growth factor receptor; pro-AREG, proamphiregulin; sAREG, soluble amphiregulin; TNFR, tumor necrosis factor receptor; MCP1, monocyte chemoattractant protein 1.