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. 2022 Nov 16;12(1):19709.
doi: 10.1038/s41598-022-24289-0.

Identification of Ribonuclease 6 as an immunoinflammatory key gene associated with the glomerular injury in diabetic nephropathy

Tongyi Li  1 , Yanmei Wang  1 , Chan Zhu  1 , Yunjiao Yang  1 , Cong Long  1 , Qiu Chen  2
Affiliations

Identification of Ribonuclease 6 as an immunoinflammatory key gene associated with the glomerular injury in diabetic nephropathy

Tongyi Li et al. Sci Rep. .

Abstract

Diabetic nephropathy is one of the major causes of end-stage renal disease, and the pathogenesis of the disease has not been elucidated. While the immunoinflammatory response plays an essential role in the progression of diabetic nephropathy. Glomerular expression dataset in diabetic nephropathy was obtained from the GEO database. Differentially expressed genes were identified and functional enrichment analysis was performed to find genes associated with immunity and inflammation from them. The hub genes of immunoinflammatory were identified using MCODE after establishing the PPI network and gene expression was verified with diabetic nephropathy model rats. Xcell was used to assign immune cells to diabetic nephropathy glomerular samples to detect significant changes in immune cells and to analyze correlations with the hub gene. We found 120 DEGs associated with immunity and inflammation, Ribonuclease 6 was the Hub gene with the highest MCODE score. Xcell analysis revealed significant changes of immune cells in DN glomeruli, including upregulated Activated DCs, Conventional DCs, CD4+ Tem, Epithelial cells, Macrophages, Macrophages M1, and Memory B-cells. RNase6 expression showed the highest positive correlation with Macrophages M1, Activated DCs, and Conventional DCs. We verified through the Nephroseq v5 database that RNase6 expression was elevated in DN glomeruli and negatively correlated with glomerular filtration rate. Animal studies revealed that the kidney of DN model rats showed increased RNase6 expression together with inflammatory factor TNF-alpha and chemokine MCP-1. Our study identified RNase6 as a diagnostic and prognostic biomarker for diabetic nephropathy and found that it may play an essential role in the immunoinflammatory damage to the glomerulus.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Comparison of differentially expressed genes between the control and DN groups. (A) Volcano plot of all differentially expressed genes for dataset GSE30528. (B) Heatmap of 120 genes associated with immunity and inflammation.
Figure 2
Figure 2
The key functional module with the highest MCODE score.
Figure 3
Figure 3
Functional enrichment analyses. (A) GO term enrichment analysis results for the top 30 GO terms, including the top 10 BPs, CCs, and MFs. (B) Enrichment analysis of immune processes for genes associated with inflammation. (C,D) KEGG pathway enrichment results and their interrelationships.
Figure 4
Figure 4
Immune cell infiltration in DN glomeruli analyzed by xCell. (A) Comparison of xCell scores of 64 cell types in the glomeruli between DN and control group in the GSE30528 dataset. (B) The heatmap represents the cell type enrichment score for each cell type of all samples.
Figure 5
Figure 5
Correlation of the key gene with differentially expressed immune cells.
Figure 6
Figure 6
(A) t-SNE dimensionality reduction analysis and information on cell subgroups. (B) Expression of RNase6 among different cell subpopulations in the two groups. (C) t-SNE dimensionality reduction analysis of Single cell sequencing samples of diabetic nephropathy. (D) The expression of RNase6 and different immune cell markers in different cell subgroups.
Figure 7
Figure 7
Correlation of RNase6 expression with glomerular filtration rate (GFR) in diabetic nephropathy and its diagnostic and prognostic value. (A) Correlation between RNase6 expression and GFR (Glomerulus). (B) Differences in RNase6 expression in the glomeruli of the control and DN groups. (C) Correlation between RNase6 expression and GFR (tubulointerstitium). (D) Differences in RNase6 expression in the tubulointerstitium between the control and DN groups. (E) ROC curve of RNase6 expression in DN (GSE142153,Peripheral blood mononuclear cell sample). (F) ROC curve of RNase6 expression in DN (GSE30528,Glomerulus). (G) ROC curve of RNase6 expression in DN (GSE30529,tubulointerstitium).
Figure 8
Figure 8
(A) Representative photomicrographs of TEM (magnification, ×20,000) and histology of renal sections stained with H&E, PAS (magnification, ×400) in the two groups. (B) The mRNA levels of RNase6, MCP-1, and TNF-alpha in rat kidney tissues were measured by RT-PCR (mean ± s.d., n = 10, *P < 0.05).
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