Abstract
BackgroundKidney stone disease (KSD) is a multifactorial disease involving both environmental and genetic factors, whose pathogenesis remains unclear. This study aims to explore the hub genes related to stone formation that could serve as potential therapeutic targets.MethodsBased on the GSE73680 dataset with 62 samples, differentially expressed genes (DEGs) between Randall’s plaque (RP) tissues and normal tissues were screened and weighted gene co-expression network analysis (WGCNA) was applied to identify key modules associated with KSD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to explore the biological functions. The protein–protein interaction (PPI) network was constructed to identify hub genes. Meanwhile, CIBERSORT and ssGSEA analysis were used to estimate the infiltration level of the immune cells. The correlations between hub genes and immune infiltration levels were also investigated. Finally, the top hub gene was selected for further GSEA analysis.ResultsA total of 116 DEGs, including 73 up-regulated and 43 down-regulated genes, were screened in the dataset. The red module was identified as the key module correlated with KSD. 53 genes were obtained for functional enrichment analysis by taking the intersection of DEGs and genes in the red module. GO analysis showed that these genes were mainly involved in extracellular matrix organization (ECM) and extracellular structure organization, and others. KEGG analysis revealed that the pathways of aldosterone-regulated sodium reabsorption, cell adhesion molecules, arachidonic acid (AA) metabolism, and ECM-receptor interaction were enriched. Through PPI network construction, 30 hub genes were identified. CIBERSORT analysis revealed a significantly increased proportion of M0 macrophages, while ssGSEA revealed no significant differences. Among these hub genes, SPP1, LCN2, MMP7, MUC1, SCNN1A, CLU, SLP1, LAMC2, and CYSLTR2 were positively correlated with macrophages infiltration. GSEA analysis found that positive regulation of JNK activity was enriched in RP tissues with high SPP1 expression, while negative regulation of IL-1β production was enriched in the low-SPP1 subgroup.ConclusionsThere are 30 hub genes associated with KSD, among which SPP1 is the top hub gene with the most extensive links with other hub genes. SPP1 might play a pivotal role in the pathogenesis of KSD, which is expected to become a potential therapeutic target, while its interaction with macrophages in KSD needs further investigation.
Highlights
Kidney stone disease (KSD) is one of the most common urological diseases worldwide with high incidence and recurrence rates, which contributes to a huge burdenHong et al BMC Medical Genomics (2022) 15:7 on the medical and health care system [1–3]
This study will use weighted gene co-expression network analysis (WGCNA) for the first time to explore key modules significantly correlated with KSD, screen hub genes in the protein–protein interaction (PPI) network, and evaluate immune infiltration levels in Randall’s plaque (RP) tissues by CIBERSORT and single-sample gene set enrichment analysis
Identification of differentially expressed genes (DEGs) After differential analysis was performed by the “limma” R package with the threshold of false discovery rate (FDR) < 0.05 and |log2FC| > 1, the difference between 29 RP papillary tissues and 33 normal papillary tissues were presented in a volcano plot (Fig. 2A)
Summary
Kidney stone disease (KSD) is one of the most common urological diseases worldwide with high incidence and recurrence rates, which contributes to a huge burdenHong et al BMC Medical Genomics (2022) 15:7 on the medical and health care system [1–3]. Kidney stone disease (KSD) is one of the most common urological diseases worldwide with high incidence and recurrence rates, which contributes to a huge burden. As an important modulator of biomineralization, SPP1 is thought to be involved in stone formation, since RP is considered as a form of pathological biomineralization [9]. Previous studies showed that SPP1 played a dual role in promoting or inhibiting crystallization [10]. Macrophage polarization is confirmed to play an important role in the development of KSD [11]. No study has investigated the relationship between SPP1 and macrophages in KSD, which needs to be fully explored. Kidney stone disease (KSD) is a multifactorial disease involving both environmental and genetic factors, whose pathogenesis remains unclear. This study aims to explore the hub genes related to stone formation that could serve as potential therapeutic targets
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