Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation.

Xuejuan Li,Suxia Wang,Jie Ding,Fangrui Ding,Baihong Li

doi:10.1038/srep17694

Xuejuan Li, Suxia Wang + Show 3 more

Open Access

https://doi.org/10.1038/srep17694

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Abstract

Accumulating evidence suggests that podocytes are direct targets of many classic antiproteinuric drugs. The immunosuppressive drug cyclosporine A (CsA), which is a calcineurin inhibitor, is used to treat proteinuric kidney diseases. One novel mechanism by which CsA reduces proteinuria is by directly stabilizing the podocyte cytoskeleton. Previous studies showed that calcineurin can directly regulate WAVE1 within mouse striatal slices. In this study, WAVE1 was expressed in podocytes and was localized in the podocyte cell bodies and foot processes (FPs). WAVE1 expression increased in both in vivo and in vitro models of puromycin aminonucleoside (PAN)-induced podocyte injury. CsA restored WAVE1 expression and also partially rescued the disordered F-actin arrangement after PAN injury. Co-immunoprecipitation assays showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes. Synaptopodin is a well-characterized target of CsA. WAVE1 overexpression and synaptopodin knockdown experiments directly demonstrated that WAVE1 expression is not dependent on synaptopodin expression, and vice versa. Overexpression of WAVE1 using a WAVE1 plasmid disrupted F-actin structure and promoted podocyte migration compared with the empty vector group. Therefore, WAVE1 may be a novel molecular target for the maintenance of podocyte FPs and for antiproteinuric treatment in the future.

Highlights

WAVE1 regulates actin reorganization downstream of the Rho family GTPase Rac
We investigated the involvement of the calcineurin-WAVE1 interaction and WAVE1 phosphorylation in the regulation of podocyte injury by ascertaining whether calcineurin directly interacts with WAVE1 in podocytes
Immunoelectron microscopy (IEM) on normal rat kidney sections revealed that the majority of WAVE1 labelling was in podocyte cell bodies and foot process (FP)

Summary

Introduction

WAVE1 regulates actin reorganization downstream of the Rho family GTPase Rac. WAVE1 regulates actin reorganization downstream of the Rho family GTPase Rac Soon after, they reported that WAVE is a phosphoprotein whose phosphorylation increased in Swiss 3T3 cells stimulated with platelet-derived growth factor, which activated mitogen-activated protein (MAP) kinase signaling[20]. Whether WAVE1 is a novel substrate in the regulation of the podocyte cytoskeleton is unknown, as is its expression in podocytes. We report the expression and distribution of WAVE1 in kidney glomerular podocytes. We demonstrated that WAVE1 might be involved in podocyte injury and might regulate the stabilization of the podocyte actin cytoskeleton. We showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes

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