Abstract
BACKGROUND: Lupus nephritis (LN) is the most common and severe clinical manifestation of systemic lupus erythematosus (SLE) with considerable morbidity/mortality and limited treatment options. Since kidney biopsy is a relative hysteretic indicator, it is indispensable to investigate potential biomarkers for early diagnosis and predicting clinical outcomes of LN patients. Extracellular proteins may become the promising biomarkers by the secretion into body fluid. Our study linked extracellular proteins with lupus nephritis to identify the emerging biomarkers. METHODS: The expression profiling data were acquired from the Gene Expression Omnibus (GEO) database. Meanwhile, the two gene lists encoding extracellular proteins were collected from the Human Protein Atlas (HPA) and UniProt database. Subsequently, the extracellular protein-differentially expressed genes (EP-DEGs) were screened out, and the key EP-DEGs were determined by MCODE, MCC, and Degree methods via the protein-protein interaction (PPI) network. The expression level, immune characteristics, and diagnostic value of these candidate biomarkers were investigated. Finally, the Nephroseq V5 tool was applied to evaluate the clinical significance of the key EP-DEGs. RESULTS: A total of 164 DEGs were acquired by comparing LN samples with healthy controls based on GSE32591 datasets. Then, 38 EP-DEGs were screened out through the intersection between DEGs and extracellular protein gene lists. Function enrichment analysis indicated that these EP-DEGs might participate in immune response and constitute the extracellular matrix. Four key EP-DEGs (LUM, TGFBI, COL1A2, and POSTN) were eventually identified as candidate biomarkers, and they were all overexpressed in LN samples. Except that LUM expression was negatively correlated with most of the immune regulatory genes, there was a positive correlation between the remaining three biomarkers and the immune regulatory genes. In addition, these biomarkers had high diagnostic value, especially the AUC value of the LUM-TGFBI combination which reached almost 1 (AUC = 0.973), demonstrating high accuracy in distinguishing LN from controls. Finally, we found a meaningful correlation of these biomarkers with sex, WHO class, and renal function such as glomerular filtration rate (GFR), serum creatinine level, and proteinuria. CONCLUSION: In summary, our study comprehensively identified four key EP-DEGs exerting a vital role in LN diagnosis and pathogenesis and serving as promising therapeutic targets.