Effects And Mechanism Of Tripterysium Wilfordii Polyglucoside On Proteinuria Induced By Bevacizumab

Backgroud Anti-angiogenic therapy has been applied to clinical therapy widely during the past decade.Bevacizumab,a novel anti-vascular endothelial growth factor for humanized monoclonal antibodies,through the selective combination of vascular endothelial growth factor(VEGF)and then prevent VEGF and its receptor combination,which making the downstream signaling pathway blocked.Bevacizumab plays the important role in anti-neovascularization and thus inhibit tumor growth.Proteinuria is one of the adverse effects induced by bevacizumab,which can lead to discontinuation or delay in the treatment of anti-angiogenesis.Patients with severe proteinuria need to permanently stop anti-angiogenesis therapy,which will seriously affect clinical efficacy.A number of studies have shown that Tripterysium wilfordii polyglucoside(TWP)can protect podocyte to alleviate proteinuria in diabetic nephropathy.TWP plays a unique role in the treatment of moderate to severe proteinuria with short onset,fastly,sustainablily effective and so on.This study was to investigate the protective effect of TWP on renal injury induced by bevacizumab in mice and to explore its mechanism.Purpose Angiogenesis inhibition has become an innovative target in cancer therapy.One of the most widely used angiogenesis inhibitors is bevacizumab(BEV).However,BEV treatment is frequently associated with the development of proteinuria.In this study,we used mice model to assess whether Tripterysium wilfordii polyglucoside(TWP)exert protective effects in proteinuria and renal injury.Methods Thirty Institute of Cancer Research(ICR)mice were randomly divided into five groups:control group: 6 ICR treated with same volume of saline;BEV group,6 ICR treated with BEV(60mg/kg·w-1);BEV-TWP1,6 ICR treated with BEV(60mg/kg·w-1 i.v)and TWP(4mg/kg/d-1);BEV-TWP2,6 ICR treated with BEV(60mg/kg·w-1i.v.)and TWP(8mg/kg/d-1);BEV-TWP3,6 ICR treated with BEV(60mg/kg·w-1 i.v.)and TWP(16mg/kg/d-1).After four weeks,24-h proteinuria,bloodureanitrogen(BUN),creatinine(Scr),glutamic-pyruvic transaminase(ALT)and glutamic oxalacetic transaminase(AST)were determined.Renal pathological changes were evaluated by hematoxylin-eosin staining.Structural change in podocytes were observed by transmission electron microscop.The expressions of(VEGF),nephrin and podocin were detected by immunohistochemical staining and quantitative RT-PCR.Results After four weeks,24-h proteinuria in BEV group was significantly higher than in control group,while the additional administration of TWP resulted in the significant reduction of proteinuria in BEV-TWP2 group and BEV-TWP3 group compared with BEV group(p<0.01).No significant differences in Scr?BUN?ALT and AST level among the five groups(p>0.05).Under the observation of optical microscopy,the kidney had normal structure in control group,showed no significant pathologic changes in BEV-TWP2 group and BEV-TWP3 group,and appeared as bulb with atrophic glomerular endothelial cells in BEV group.Immunohistochemical analysis demonstrated the expression of VEGF/podocin and podocin was medium or strong positive in control,BEV-TWP2 and BEV-TWP3 groups,while weak positive or negative in BEV group.Podocytes of mice in BEV group were observed extensively fused.Furthermore,immunohistochemical staining and quantitative RT-PCR results revealed that the expression levels of nephrin and podocin in mouse kidneys were inversely associated with proteinuria in all these 5 groups.Conclusions Bevacizumab was proved to down-regulate expressions of VEGF,nephrin and podocin and induce renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria.TWP may exert a protective effect on podocytes in mice.The mechanism may be associated with the up-regulated expressions of VEGF,nephrin and podocin.