Identification of genes related to tubulointerstitial injury in type 2 diabetic nephropathy based on bioinformatics and machine learning

Objective:To explore the genes related to renal tubulointerstitial injury in DN and to elucidate their underlying mechanism by using bioinformatics multi-chip joint analysis and machine learning technology,so as to provide new ideas for the diagnosis and treatment of DN.Methods:Four gene expression datasets of DN tubulointerstitial tissues were retrieved from the GEO database.GSE30122,GSE47185 and GSE99340 were used as the combined microarray datasets,and GSE104954 was used as the independent verification datasets.The differentially expressed genes(DEGs)were identified by R language,and Gene Ontology(GO)enrichment,KEGG pathway enrichment,Gene Set Enrichment Analysis(GSEA)and Immune Cell Infiltration Analysis were performed.Furthermore,LASSO regression,SVM-RFE and RF machine learning algorithm were used to screen core genes,while external validation and Receiver Operating Curve(ROC)analysis as well as the model of prediction nomogram were performed.Finally,the influence of the clinical characteristics of DN patients was explored by Nephroseq.Results:A total of 107 DEGs were obtained,enrichment analysis revealed that the tubulointerstitial injury in DN was mainly involved in adaptive immune response,lymphocyte mediated immunity,regulation of immune effector process and immune-inflammatory pathways such as staphylococcus aureus infection,complement and coagulation cascades,phagosomes,and Th1 and Th2 cell differentiation.In addition,cell adhesion molecule,cytokine-cytokine receptor interaction and ECM-receptor interaction pathways were also significantly enriched.Memory resting CD4 T cells,γδ毮T cells,resting mast cells and neutrophil cells were up-regulated,while CD8 T cells were down-regulated.Machine learning identified MARCKSL1,CX3CR1,FSTL1,AGR2,GADD45B as core genes with good diagnostic and predictive efficacy.Conclusion:The key pathological mechanism of tubulointerstitial injury in DN is immune disorder,inflammatory reaction,cytokine action and extracellular matrix deposition.Moreover,MARCKSL1,CX3CR1,FSTL1 may be the potential biomarkers for the diagnosis and prediction of DN.

Repetitive administration of cultured human CD34+cells improve adenine-induced kidney injury in mice

BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease(CKD).AIM To examine the efficacy of cultured human CD34+cells with enhanced proliferating potential in kidney injury in mice.METHODS Human umbilical cord blood(UCB)-derived CD34+cells were incubated for one week in vasculogenic conditioning medium.Vasculogenic culture significantly increased the number of CD34+cells and their ability to form endothelial progenitor cell colony-forming units.Adenineinduced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice,and cultured human UCB-CD34+cells were administered at a dose of 1×106/mouse on days 7,14,and 21 after the start of adenine diet.RESULTS Repetitive administration of cultured UCB-CD34+cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group.Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group(P<0.01).Microvasculature integrity was significantly preserved(P<0.01)and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group(P<0.001).CONCLUSION Early intervention using human cultured CD34+cells significantly improved the progression of tubulointerstitial kidney injury.Repetitive administration of cultured human UCB-CD34+cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.