The Epidermal Growth Factor Receptor (EGFR) is a member of the family of ErbB receptors, which consist of an extracellular ligand-binding domain, a single membrane-spanning region, a homologic cytoplasmic protein tyrosine kinase domain and a C-terminal tail with multiple phosphorylation sites. EGFR can be activated by a family of ligands (including EGF, TGF-a, HB-EGF, amphiregulin, epiregulin and betacellulin) that bind and induce receptor autophosphorylation and activation of intracellular signaling pathways. Transactivation of the EGFR receptor occurs by activation of ADAM-mediated cleavage and release of active EGFR ligands, with ADAM17 (TACE) mediating release of HB-EGF, amphiregulin, TGF-a and epiregulin. We and others have reported EGFR to be a mediator of fibrosis in chronic progressive kidney disease, including diabetic nephropathy, RPGN, chronic allograft nephropathy and PKD. Either genetic or pharmacologic inhibition of EGFR activation can be an effective therapeutic intervention in experimental models of progressive kidney disease, but the mechanisms by which EGFR activation mediates development of progressive chronic kidney injury are still incompletely understood. EGFR and its ligands are expressed in a variety of cell types including cells of myeloid origin. We and others have defined an important role for myeloid derived cells in propagation of acute kidney injury and in the development of chronic renal damage, but the role of renal myeloid cell EGFR and its ligands in progressive kidney injury has not been previously studied. Our recent preliminary studies indicate that EGFR signaling is a mediator of inflammatory macrophage actions in the kidney. As indicated in Preliminary Results, activation of myeloid EGFR as well as expression of its ligand, amphiregulin (AREG), appear to play an important role in post-ischemic renal injury and in development of progressive renal fibrosis. In addition, recent studies demonstrate that iRhom2, an inactive member of the Rhomboid intramembrane proteinase family, mediates myeloid cell-specific activation of TACE and secretion of amphiregulin and HB-EGF, as well as TNF-a without affecting ligand release in other organs, raising the possibility that targeting iRhom2 could be a potentially efficacious approach to limit development or progression of CKD. We propose to investigate the role of the renal myeloid EGFR axis in development of chronic renal fibrosis in three specific aims:
Aim I Determine the role of EGFR in macrophage activation in kidney disease Aim II Determine the role of amphiregulin in mediation of development of tubulointerstitial fibrosis with progressive kidney injury Aim III Determine the role of iRhom2 (Rhomboid 5 homolog 2 (RHBDF2)) activation in mediation of renal myeloid cell-mediated tubulointerstitial fibrosis
The proposed studies will investigate the role of the epidermal growth factor receptor (EGFR) and its ligands in mediation of renal macrophage activity in both acute and chronic kidney injury. The studies will investigate mechanisms of macrophage EGFR activation and polarization of macrophages following renal injury, and the role of release of the EGFR ligand, amphiregulin in mediating tubulointerstitial fibrosis.
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