SUN-164 CXCR4-AngII axis plays an important role in glomerular injury through promoting the crosstalk between podocytes and mesangial cells

Abstract

Glomerular disease has a high incidence worldwide. Podocyte injury and mesangial cell activation play pivotal roles in the progression of proteinuria and glomerulosclerosis. However, the linkage and underlying mechanisms are rarely reported. Herein, we investigated the role of chemokine receptor (CXCR4) and angiotensin II (AngII) in the pathogenesis of podocyte and mesangial cell injury. The association of CXCR4-AngII axis in crosstalk between podocytes and mesangial cells was also testified. 5/6 nephrectomized mice was established. To identify the role of CXCR4, CXCR4 plasmid was injected once a week by tail injection. Some mice were injected with adriamycin (ADR), advanced oxidation protein products (AOPPs) or Losartan. In vitro, MPC5 cells, an immortalized mouse podocyte cell line, were incubated with AOPPs or transfected with CXCR4 expression plasmid or siRNA to CXCR4. RMC cells, an immortalized mesangial cell line, were also adopted. RMC were treated with the conditional medium from AOPPs-treated MPC5 cells to assess the crosstalk between podocytes and mesangial cells. In 5/6NX and ADR mice model, CXCR4 was upregulated predominantly in podocytes. Whereas, SDF-1α, the ligand of CXCR4, was highly expressed in mesangial cells. CXCR4 colocalized with AngII in podocytes. Administration of AOPPs significantly induced the upregulation of CXCR4 and accelerated the progression of proteinuria. AOPPs induced podocyte injury and mesangial cell proliferation. These glomerular lesions were accompanied by upregulation of CXCR4, SDF-1α and activation of ACE, Renin and AT1. In ADR model, ectopic expression of CXCR4 aggravated proteinuria, podocyte injury, mesangial cell proliferation and glomerulosclerosis. Treatment with losartan significantly ameliorated these pathological changes. In cultured MPC5 cells, incubation of AOPPs or overexpression of CXCR4 promoted the activation of ACE, Renin, and AT1. However, blockade of CXCR4 reduced these effects. In RMC cells, administration of AngII stimulated fibrogenesis and cell proliferation. The conditional medium from AOPPs-treated MPC5 cells induced upregulation of fibronectin, PCNA and angiotensin II receptor AT1, but blocked by incubation with losartan. Our studies indicate that CXCR4 could upregulate the expression of RAS system in podocyte. AngII may subsequently bind to its receptor AT1 in mesangial cells to induce matrix deposition. The activation of mesangial cells would lead to the secretion of SDF-1α, the ligand of CXCR4, which further triggers podocyte injury. These studies demonstrate that CXCR4-AngII axis plays a vital role in glomerular injury via mediating pathologic crosstalk between podocytes and mesangial cells. Our findings uncover a new pathogenic mechanism by which CXCR4-AngII axis promotes glomerulosclerosis.