CD38 Promotes The Role And Mechanism Of Kidney Injury By Regulating The Activation Of Macrophages

Lupus nephritis is a chronic autoimmune disorder with disturbances in both innate and adaptive immunity.Among of them,the infiltrated inflammatory cells,especially activated macrophages are mainly observed in glomerular and tubulointerstitial area.However,the role and mechanisms for macrophage in regulating lupus nephritis progression and pathogenesis remain largely unknown.Here we try to identify the candidate genes in macrophages from lupus nephritis.We performed a systematic search in the Gene Expression Omnibus(GEO)database for microarray in human mononuclear cells and mouse macrophages of lupus nephritis.The results of clustering and venn analysis of different GEO datasets showed that 8 genes were up-regulated and 2 genes down-regulated in samples from both human and mouse lupus nephritis.The data from gene network and GO analysis revealed that CD38 and CCL2 were localized in the core of the network.Next,we searched the RGD Disease Portals database,Lupus Nephritis category,the previous studies exhibited that the CCL2 has been confirmed to participate in pathogenesis of lupus nephritis.Immunofluorescence staining showed that CD38 expression was markedly increased in macrophages from kidneys with lupus nephritis.Together,these results demonstrated that CD38 is significantly up-regulated and activated in macrophage from kidney of LN and may become new target in treatment disease.The bioinformatics analysis could provide new strategies to investigate the candidate genes and mechanisms that could regulate the pathogenesis of diseases.The CD38,possessing ADP-ribosyl cyclase(ADPR-cyclase)and cyclic ADP-ribose hydrolase(cADPR-hydrolase),is able to regulate a variety of cellular activities.However,the role and mechanisms for CD38 in macrophage activation and sepsis-induced acute kidney injury(AKI)remain to be determined.Here,we found that LPS could up-regulate CD38 expression in cultured Raw 264.7 cells,a mice macrophage cell line,with a time-and dose-dependent manner.Knocking down or inhibition of CD38 with Quercetin in macrophage could reduce the NF-? B signal pathway activation and M1 polarization after LPS stimulation.In vivo,LPS intraperitoneally injection could induce severe renal dysfunction and pathological damage.CD38 inhibitor quercetin injection could alleviate elevation of blood urea nitrogen(BUN).Interestingly,HE and PAS staining and immunofluorescence results demonstrated that CD38 inhibitor Quercetin could significantly improve tubular injury and renal capsule cavity dilation after LPS injection.Most notably,macrophage and neutrophil infiltration and proinflammatory cytokines expression such as RANTES,TNF-a and MCP-1 were also remarkably inhibited in the LPS injection mice treated with CD38 inhibitor.What's more,the mRNA abundance of markers for M1 macrophages,iNOS,IL-6,IL-1?,and IL-12? in macrophages sorted from kidneys and spleens,were significantly down-regulated in LPS+Quercetin group compared with LPS group.In addition,inhibitor treatment alleviate the effect of LPS induced NF-K B signal pathway activation in macrophage from kidneys and spleens.Taken together,these results demonstrate that CD38 in macrophage act an important role in regulating the progression of LPS-induced AKI which may through NF-? B signal pathway activation.