Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Abstract

Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis and accelerates the progression of chronic kidney disease; however, the underlying molecular mechanism is poorly understood. Angiotensin II (Ang II), the central component of RAS, is a key regulator of renal fibrogenic destruction. Here we show that epidermal growth factor receptor (EGFR) plays an important role in Ang II-induced renal fibrosis. Inhibition of EGFR activation by novel small molecules or by short hairpin RNA knockdown in Ang II-treated SV40 mesangial cells in vitro suppresses protein kinase B and extracellular signal-related kinase signaling pathways and transforming growth factor-b/Sma-and Mad-related protein activation, and abolishes the accumulation of fibrotic markers such as connective tissue growth factor, collagen IV. The transactivation of EGFR by Ang II in SV40 cells depends on the phosphorylation of proto-oncogene tyrosine-protein kinase Src (c-Src) kinase. Further validation in vivo demonstrates that EGFR small molecule inhibitor successfully attenuates renal fibrosis and kidney dysfunction in a mouse model induced by Ang II infusion. These findings indicate a crucial role of EGFR in Ang II-dependent renal deterioration, and reveal EGFR inhibition as a new therapeutic strategy for preventing progression of chronic renal diseases.

The epidermal growth factor receptor pathway in chronic kidney diseases

“…Although the mechanism by which Ang II activates EGFR signalling is still unclear, a possible explanation might be that upon Ang II signalling, ADAM 17 becomes active and consequently activates TGFα, thereby initiating EGFR signalling 55 . In addition, EGFRstimulated renal fibro sis can also be Ang II independent, as EGF stimulation alone could induce markers of fibrosis in SV40 cells 54 .…”

“…In addition, mice with specific endothelial Hbegf deletion had significantly less albuminuria, glomerulosclerosis and renal fibrosis in response to chronic Ang II infusion than did wildtype mice 53 . In mice with Ang IIinduced renal fibrosis, several specific EGFR small molecule inhibitors (AG1478, AG451, and AG557) attenuated renal fibro sis and reduced the kidney to total body weight ratio 54 . Although the mechanism by which Ang II activates EGFR signalling is still unclear, a possible explanation might be that upon Ang II signalling, ADAM 17 becomes active and consequently activates TGFα, thereby initiating EGFR signalling 55 .…”

“…In vivo activation of the EGFR in the kid neys results in local upregulation of proinflammatory factors and infiltration of inflammatory cells 56 . Besides the involvement of EGFR signalling in renal fibrosis and inflammation, the EGFR receptor contributes to renal cell proliferation, and activation of EGFR is one of the major triggers for tubular cell proliferation 54 . Cystic epi thelial cells obtained from patients with polycystic kid ney disease (PKD) hyperproliferate when stimulated by EGF in culture 15 .…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…In cell culture, soluble HB-EGF or EGFR transactivation by ANG II induces dedifferentiation of inner medullary collecting duct cells or proximal tubule epithelial cells (86, 90, 517). In vivo, both renal proximal tubule epithelial cell EGFR deletion mice and administration of an EGFR tyrosine kinase inhibitor to mice attenuated ANG II-induced kidney fibrosis (445).…”

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

“…1a). We have recently shown that these inhibitors effectively block EGFR activation and attenuate angiotensin II-induced cardiac hypertrophy and dysfunction21. We have further delineated a novel mode of EGFR activation in atherosclerosis.…”