Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies

Abstract

Epidermal growth factor receptor (EGFR), which is referred to as ErbB1/HER1, is the prototype of the EGFR family of receptor tyrosine kinases which also comprises ErbB2 (Neu, HER2), ErbB3 (HER3), and ErbB4 (HER4). EGFR, along with other ErbBs, is expressed in the kidney tubules and is physiologically involved in nephrogenesis and tissue repair, mainly following acute kidney injury. However, its sustained activation is linked to several kidney pathologies, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, chronic kidney disease, and renal fibrosis. This review aims to provide a summary of the recent findings regarding the consequences of EGFR activation in several key renal pathologies. We also discuss the potential interplay between EGFR and the reno-protective angiotensin-(1-7) (Ang-(1-7), a heptapeptide member of the renin-angiotensin-aldosterone system that counter-regulates the actions of angiotensin II. Ang-(1-7)-mediated inhibition of EGFR transactivation might represent a potential mechanism of action for its renoprotection. Our review suggests that there is a significant body of evidence supporting the potential inhibition of EGFR/ErbB, and/or administration of Ang-(1-7), as potential novel therapeutic strategies in the treatment of renal pathologies. Thus, EGFR inhibitors such as Gefitinib and Erlinotib that have an acceptable safety profile and have been clinically used in cancer chemotherapy since their FDA approval in the early 2000s, might be considered for repurposing in the treatment of renal pathologies.

Keywords: ErbB; acute kidney injury (AKI); chronic kidney disease; diabetic nephropathy; epidermal growth factor receptor; glomerulonephritis; hypertensive nephropathy; renal fibrosis.

FIGURE 1

The arrangement and cognate ligands of the ErbB family of receptors. An ErbB receptor is composed of an extracellular domain that binds specific ligands, a transcellular component, and an intracellular domain with a tyrosine kinase activity (TK). The ErbB-2 is not known to have any ligand, while the ErbB-3 is known to lack kinase activity. Once a ligand binds the extracellular domain of ErbB receptors, it induces dimerization of the receptor (homodimerization or heterodimerization), tyrosine kinase activation (TK), trans-phosphorylation (P) and initiation of downstream signaling cascades (see main text for further details).

FIGURE 2

Distribution of ErbB family of receptors (in black text) with their corresponding ligands (in blue text) throughout the nephron. The different receptors and their ligands are differentially expressed along the various segments of the nephron (including the glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and the collecting duct) in a human adult kidney. Note the exception: HB-EGF expression data is from rat kidneys (asterisked).