Theranostics 2022; 12(2):767-781. doi:10.7150/thno.65948 This issue
1. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
3. Division of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
4. Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
*These authors contributed equally to this work.
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 β-catenin in mediating CXCR4-triggered podocyte injury.
Methods: Mouse models of proteinuric kidney diseases were used to assess CXCR4 and β-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/β-catenin in podocyte injury and proteinuria.
Results: Both CXCR4 and β-catenin were induced and colocalized in the glomerular podocytes in several models of proteinuric kidney diseases. Activation of CXCR4 by its ligand SDF-1α stimulated β-catenin activation but did not affect the expression of Wnt ligands in vitro. Blockade of β-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-1α caused the formation of CXCR4/β-arrestin-1/Src signalosome in podocytes, which led to sequential phosphorylation of Src, EGFR, ERK1/2 and GSK-3β and ultimately β-catenin stabilization and activation. Silencing β-arrestin-1 abolished this cascade of events and inhibited β-catenin in response to CXCR4 stimulation. Podocyte-specific knockout of CXCR4 in mice abolished β-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/β-arrestin-1/Src signalosome, which triggers a cascade of signal events leading to β-catenin activation.
Keywords: Podocyte, CXCR4, β-catenin, β-arrestin-1, proteinuria, glomerulosclerosis