The Role of the Epidermal Growth Factor Receptor in Kidney Tubulointerstitial Fibrosis

Kidney fibrosis is a common cause of chronic kidney disease. Experimental studies have demonstrated a role for the epidermal growth factor receptor (EGFR) signaling pathway in mediating the development and progression of kidney fibrosis. Deletion of Rhbdf2 (iRhom2), a member of the rhomboid family that regulates A disintegrin and metalloproteinase domain 17-mediated release of membrane-anchored proteins, including EGFR ligands, inhibited kidney interstitial fibrosis, which was accompanied by decreased EGFR activation in interstitial fibroblasts/myofibroblasts. In addition, overexpression of another EGFR ligand, heparin-binding epidermal growth factor-like growth factor, induced interstitial fibrosis in kidneys. Although EGFR activation did not induce myofibroblast transformation, it was necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by transforming growth factor beta or other profibrotic factors. Therefore, EGFR activation in kidney fibroblasts and pericytes serves as a specific initiator of interstitial fibrosis in response to kidney injury by stimulating pericyte/fibroblast migration and proliferation. These findings may also provide insight into the development of fibrosis in other organs and in other conditions.