Single-cell RNA-Seq Analysis Identifies Renal Immune Cell-cell Interactions in Early Diabetic Kidney Disease
To explore the impact of immune cells and intercellular interactions on the progression of diabetic kidney disease(DKD)in mice,this study employed CellChat software for the analysis of single-cell RNA-sequencing(scRNA-Seq)data.The investigation un-veiled,MIF signaling,one of three prominent signaling(CCL,MIF,and CXCL)between renal immune cells,witnessed a significant decline in the early DKD kidney,characterized by diminished expression of Mif and its receptor genes Cd44,Cxcr4,and Cxcr2.Addi-tionally,F13a1+macrophages ceased to be responsive to MIF signaling.In the early DKD kidney,F13a1+ macrophages were immune cells with the most pronounced differences in both interaction numbers and strength.Moreover,alterations of ligands in F13a1+macro-phages in DKD kidneys resulted in the disappearance of ANGPTL,IL2,and IL16 signaling,and the emergence of KIT and PROS sig-naling.Notably,it was observed that F13a1+macrophages reduced the expression of the transcription factor Etv1(ETS variant tran-scription factor 1),which is pivotal in regulating activity of immune cells.Gene set enrichment analysis(GSEA)of differentially ex-pressed genes(DEGs)revealed chemokine-mediated signaling pathways,immune response,and myeloid leukocyte mediated immunity were down-regulated.Meanwhile,the activation of immune response,phagocytosis,engulfment,and hematopoietic progenitor cell differ-entiation were up-regulated in F13a1+macrophages in early DKD kidney.Finally,validation using kidneys from mice with diet-induced diabetes demonstrated excellent reproducibility of the results,except for KIT signaling.This study reveals that in the kidneys of mice with early DKD,F13a1+macrophages change the immune related activity which partly links to reduced expression of transcription factor Etv1,and modulate immune-cell communication by modifying MIF signaling and the interactions of ligand-receptor pairs,including TSLP-(IL7R+CRLF2),IL16-CD4,ANGPTL4-SDC3/4,and PROS1-AXL,underscoring their crucial role in the initiation and progression of DKD.
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