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Background <p>Diabetic nephropathy (DN) is a progressive kidney disease triggered by high blood glucose, which involves the interaction of multiple complex molecular pathways. The aim of this study is to identify the potential biomarkers of DN using multi-omics analysis, and to investigate the role and potential molecular mechanism of the key gene lumican (LUM) in the progression of DN.</p> Methods <p>The differentially expressed genes (DEGs) were screened from Gene Expression Omnibus (GEO) database (accession: GSE30529), and the differentially expressed proteins (DEPs) were screened from ProteomeXchange website (PXD040617 dataset). The key functions and related pathways of DEGs and DEPs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Venn diagram was used to obtain intersection genes, and then hub genes were obtained according to Molecular Complex Detection (MCODE) plug-in and Degree value. The expression levels of LUM, RNA-binding motif protein 15 (RBM15), inflammation factors, ferroptosis-related markers and fibrosis-related markers were analyzed using quantitative real-time PCR or western blot. The regulation of RBM15 on LUM was confirmed by RNA immunoprecipitation (RIP) assay, methylated RNA immunoprecipitation (MeRIP) assay and dual-luciferase reporter assay. DN rat models were constructed to explore the effect of LUM knockdown on renal damage in vivo.</p> Results <p>A total of 537 DEGs and 1799 DEPs were screened in DN samples, and GO and KEGG analyses identified these DEGs and DEPs as multifunctional and related to multiple pathways. Furthermore, 110 intersection genes were screened by Venn diagram analysis, and 5 key hub genes (LUM, COL3A1, THBS1, CD44, and FN1) in DN progression were obtained according to MCODE and Degree. LUM knockdown inhibited HG-induced HK-2 cell inflammation, ferroptosis and fibrosis, as well as alleviated renal lesions in DN rat models. RBM15 enhanced LUM mRNA stability by promoting its m6A modification, and the inhibitory effect of RBM15 silencing on HG-induced HK-2 cell injury could be reversed by LUM overexpression.</p> Conclusion <p>LUM, modified by RBM15, promoted HG-induced renal cell inflammation, ferroptosis and fibrosis, suggesting that RBM15/LUM was a key regulatory axis promoting DN progression.</p> Graphical abstract <p></p>

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Integrated multi-omics analysis reveals lumican (LUM) as a diabetic nephropathy biomarker regulated by RNA-binding motif protein 15 (RBM15)

  • 期刊论文

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  • 发表日期：

    2026年6月20日

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  • Shulong Wang,
  • Yan Bao,
  • Huishu Han,
  • Lu Du,
  • Yun Wang,
  • Huilin Xing,
  • Xiangdong Liu

摘要

Background

Diabetic nephropathy (DN) is a progressive kidney disease triggered by high blood glucose, which involves the interaction of multiple complex molecular pathways. The aim of this study is to identify the potential biomarkers of DN using multi-omics analysis, and to investigate the role and potential molecular mechanism of the key gene lumican (LUM) in the progression of DN.

Methods

The differentially expressed genes (DEGs) were screened from Gene Expression Omnibus (GEO) database (accession: GSE30529), and the differentially expressed proteins (DEPs) were screened from ProteomeXchange website (PXD040617 dataset). The key functions and related pathways of DEGs and DEPs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Venn diagram was used to obtain intersection genes, and then hub genes were obtained according to Molecular Complex Detection (MCODE) plug-in and Degree value. The expression levels of LUM, RNA-binding motif protein 15 (RBM15), inflammation factors, ferroptosis-related markers and fibrosis-related markers were analyzed using quantitative real-time PCR or western blot. The regulation of RBM15 on LUM was confirmed by RNA immunoprecipitation (RIP) assay, methylated RNA immunoprecipitation (MeRIP) assay and dual-luciferase reporter assay. DN rat models were constructed to explore the effect of LUM knockdown on renal damage in vivo.

Results

A total of 537 DEGs and 1799 DEPs were screened in DN samples, and GO and KEGG analyses identified these DEGs and DEPs as multifunctional and related to multiple pathways. Furthermore, 110 intersection genes were screened by Venn diagram analysis, and 5 key hub genes (LUM, COL3A1, THBS1, CD44, and FN1) in DN progression were obtained according to MCODE and Degree. LUM knockdown inhibited HG-induced HK-2 cell inflammation, ferroptosis and fibrosis, as well as alleviated renal lesions in DN rat models. RBM15 enhanced LUM mRNA stability by promoting its m6A modification, and the inhibitory effect of RBM15 silencing on HG-induced HK-2 cell injury could be reversed by LUM overexpression.

Conclusion

LUM, modified by RBM15, promoted HG-induced renal cell inflammation, ferroptosis and fibrosis, suggesting that RBM15/LUM was a key regulatory axis promoting DN progression.

Graphical abstract