CXCR4-AngⅡ Axis Plays An Important Role In Glomerular Injury Through Promoting The Crosstalk Between Podocytes And Mesangial Cells

Background and ObjectiveGlomerular disease has a high incidence worldwide.Characterizing by the deficiency of glomerular filtration barrier and expansion of mesangial matrix,glomerular injury mainly results from podocyte injury and mesangial cell activation.Notably,they are commonly accompanied and would have internal linkage.However,the interdependency and underlying mechanisms are rarely reported.Herein,we investigated the role of chemokine receptor CXCR4 and angiotensin Ⅱ(AngⅡ)in the pathogenesis of crosstalk between podocytes and mesangial cells.MethodsAdriamycin(ADR)mice,db/db mice or 5/6 nephrectomized mice model was established.To identify the role of CXCR4,CXCR4 plasmid was injected once a week by tail injection.Some mice were injected with advanced oxidation protein products(AOPPs)or losartan,an AT1 blocker.In vitro,MPC5,an immortalized mouse podocyte cell line,were transfected with the CXCR4 expression plasmid(pFlagCXCR4),or mouse CXCR4 siRNA or mouse NOX4 shRNA plasmid with lipofectamine 2000.RMC cells,an immortalized rat mesangial cell line,were treated with the conditional medium from AOPPs-treated MPC5 cells or losartan.ResultsIn 5/6NX,ADR mice model and db/db mice model,We found CXCR4 and renin angiotensin system(RAS)activity were upregulated in podocytes.Although initially expressed in podocytes,type 1 angiotensin receptor(AT1)and SDF-lα,the ligand of CXCR4,were evidently upregulated in mesangial cells following the progression of glomerular sclerosis.Administration of advanced oxidation protein products(AOPPs),an oxidative stress inducer,or ectopic expression of CXCR4 could accelerate these effects.While treatment of losartan,an AT1 blocker,interrupted the cycle of podocyte injury and mesangial matrix deposition triggered by CXCR4.In vitro,the conditional medium from AOPPs-induced podocytes could trigger mesangial cell activation,which was blocked by pre-knockdown of CXCR4 in cultured podocytes.In cultured mesangial cells,AngⅡ treatment induced the expression of SDF-1α,which was secreted into the supernatant to further promote oxidative stress and cell injury in podocytes.ConclusionsOur studies indicate that CXCR4 could activate RAS system in podocyte.AngⅡmay 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 glomerular injury.