EGF Receptor Activation Stimulates SOX9 Expression in Injured Renal Proximal Tubule Epithelial Cells

Key Points Upregulation and colocalization of EGF receptor and SOX9 were exhibited in injured renal proximal tubule epithelial cells (RPTCs). Genetic or pharmacologic inhibition of EGF receptor activation in mice blocked SOX9 upregulation in the ischemic injured RPTCs. Inhibition of yes-associated protein/transcriptional coactivator with PDZ-binding motif–transcriptional enhanced associate domain in mice or cultured RPTCs blocked SOX9 upregulation in response to ischemic AKI or EGF treatment. Background In surviving renal proximal tubule cells (RPTCs) after AKI, the induction of SOX9 expression plays a crucial role in promoting kidney repair. However, persistent upregulation of SOX9 in RPTCs contributes to the development of CKD. The molecular mechanisms underlying SOX9 induction in response to kidney injury are not completely understood. We and others have previously reported that the activation of EGF receptor (EGFR) in RPTCs can accelerate kidney recovery from ischemic injury, but persistent EGFR activation leads to tubulointerstitial fibrosis. Methods We examined SOX9 and EGFR expression in renal tubular epithelial cells of patients with acute tubular injury or early stages of chronic allograft nephropathy. We investigated the role of EGFR activation in regulating SOX9 upregulation in injured RPTCs using different mouse models. We further confirmed the underlying mechanism by which EGFR activation upregulates SOX9 expression in cultured human RPTCs. Results Elevation and colocalization of SOX9 and EGFR expression were detected in renal tubular epithelial cells of patients with acute tubular injury or early stages of chronic allograft nephropathy. Overexpression of human heparin-binding EGF in RPTC of mice led to increased SOX9 expression, which was abolished when these mice were crossed with EGFR tyrosine kinase–deficient waved2 mice. Genetic or pharmacologic inhibition of EGFR resulted in decreased SOX9 expression in renal tubular cells in response to ischemic AKI. Mechanistically, ischemic AKI activates proximal tubule EGFR, leading to the activation of Akt–yes-associated protein/transcriptional coactivator with PDZ-binding motif–transcriptional enhanced associate domain pathway and the subsequent induction of SOX9. Conclusions EGFR activation is crucial for SOX9 expression in RPTCs after AKI.