CXCR4 induces podocyte injury and proteinuria by activating β-catenin signaling

Background: C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in mediating podocyte dysfunction, proteinuria and glomerulosclerosis. However, the underlying mechanism remains poorly understood. Here we studied the role of beta-catenin in mediating CXCR4-triggered podocyte injury. Methods: Mouse models of proteinuric kidney diseases were used to assess CXCR4 and beta-catenin expression. We utilized cultured podocytes and glomeruli to delineate the signal pathways involved. Conditional knockout mice with podocyte-specific deletion of CXCR4 were generated and used to corroborate a role of CXCR4/beta-catenin in podocyte injury and proteinuria. Results: Both CXCR4 and beta-catenin were induced and colocalized in the glomerular podocytes in several models of proteinuric kidney diseases. Activation of CXCR4 by its ligand SDF-1 alpha stimulated beta-catenin activation but did not affect the expression of Wnt ligands in vitro. Blockade of beta-catenin signaling by ICG-001 preserved podocyte signature proteins and inhibited Snail1 and MMP-7 expression in vitro and ex vivo. Mechanistically, activation of CXCR4 by SDF-1 alpha caused the formation of CXCR4/beta-arrestin-1/Src signalosome in podocytes, which led to sequential phosphorylation of Src, EGFR, ERK1/2 and GSK-3 beta and ultimately beta-catenin stabilization and activation. Silencing beta-arrestin-1 abolished this cascade of events and inhibited beta-catenin in response to CXCR4 stimulation. Podocyte-specific knockout of CXCR4 in mice abolished beta-catenin activation, preserved podocyte integrity, reduced proteinuria and ameliorated glomerulosclerosis after Adriamycin injury. Conclusion: These results suggest that CXCR4 promotes podocyte dysfunction and proteinuria by assembling CXCR4/beta-arrestin-1/Src signalosome, which triggers a cascade of signal events leading to beta-catenin activation.

Automated summary

This study found that CXCR4 and beta-catenin colocalized in glomerular podocytes and that the assembly of CXCR4/beta-arrestin-1/Src signalosome led to beta-catenin activation, promoting podocyte dysfunction and proteinuria.