# Mechanisms of EGFR Activation and Signaling in Kidney Disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $598,492

## Abstract

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

## Key facts

- **NIH application ID:** 10117982
- **Project number:** 2R01DK051265-25A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RAYMOND C. HARRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $598,492
- **Award type:** 2
- **Project period:** 1997-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117982

## Citation

> US National Institutes of Health, RePORTER application 10117982, Mechanisms of EGFR Activation and Signaling in Kidney Disease (2R01DK051265-25A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117982. Licensed CC0.

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