Despite recent studies have demonstrated that the
EGF receptor (EGFR) activation provided a renoprotective role during ischemic and
folic acid-induced AKI, the role and regulation mechanism of EGFR in septic AKI remains unclear. Here,
gefitinib, a highly selective EGFR inhibitor, abrogated LPS-induced phosphorylation of EGFR, ERK1/2, and STAT3 as well as expression of COX, eNOS, and proinflammatory
cytokines in HK-2 cells. In addition, c-Src is an upstream of EGFR signaling pathway and mediates LPS-induced EGFR transactivation. In vivo, either
gefitinib or genetic approaches (Wave-2 mutant mice, which have reduced EGFR
tyrosine kinase activity) protected against LPS or cecal
ligation and
puncture (CLP) induced AKI respectively. Interestingly, the beneficial effects of
gefitinib or genetic approaches were accompanied by the dephosphorylation of EGFR, ERK1/2, and STAT3, the down regulation of expression of COX, eNOS, macrophage infiltration, proinflammatory
cytokines production and the renal cell apoptosis. Furthermore,
mRNA array results indicated that gene families involved in cell death,
inflammation, proliferation and signal transduction were down regulated in Wave-2 (Wa-2) mice. Take together, these data suggest that EGFR may mediate renal injury by promoting production of inflammatory factors and cell apoptosis. Inhibition of EGFR may have therapeutic potential for AKI during
endotoxemia.