Identifying the hub genes in macrophage infiltration and verifying of the role of VSIG4 in IgA nephropathy.

Abstract

Macrophage infiltration is critically involved in the pathogene and progression of IgA nephropathy (IgAN). However, the underlying molecular mechanisms remains unclear. This study aimed to identify hub genes associated with macrophage infiltration in IgAN. We further sought to validate a key candidate, VSIG4, and to elucidate its expression pattern and functional role in the disease. Datasets for IgAN were sourced from the GEO database. Differentially expressed genes (DEGs) and Macrophage-related hub genes were identified, and their correlation with clinical characteristics was analyzed for searching biomarkers. The IgAN rat model was established to investigate the expression and distribution of hub genes in renal tissue and serum. An IgAN cohort comprised of 107 patients and 55 normal humans was conducted for validating. From two available datasets, 153 DEGs were identified and mostly enriched in the complement and coagulation cascades pathway. Three macrophage-related hub genes (C1QA, C1QB, and VSIG4) were up-regulated in IgAN, with VSIG4 showing the closest connection with clinical features, which dramatically negatively correlated with GFR (p&#x2009;=&#x2009;0.004, r=-0.825). The expression of VSIG4, which encoded by VSIG4, was up-regulated in both the renal tissues and serum of IgAN rats, while VSIG4 primarily co-localized in the renal interstitium with the macrophage marker. A total of 107 IgAN patients were included, with the urinary VSIG4 levels elevated in IgAN patients, which showed negatively correlated with eGFR ( r = -0.272, P.adj&#x2009;=&#x2009;0.013 ), while positively correlated with serum creatinine ( r&#x2009;=&#x2009;0.292, P.adj&#x2009;=&#x2009;0.009 ), 24&#xa0;h urinary protein ( r&#x2009;=&#x2009;0.273, P.adj&#x2009;=&#x2009;0.013 ) and Oxford pathological classification T ( r&#x2009;=&#x2009;0.227, P.adj&#x2009;=&#x2009;0.019 ). The ROC curve indicated an AUC of 0.796 (95% CI: 0.729-0.864, P&#x2009;<&#x2009;0.001) for urinary VSIG4 in diagnosing IgAN. VSIG4 is a crucial hub gene that affects macrophage infiltration in IgAN patients. It is highly expressed in IgAN and is closely related to various clinicopathological features. VSIG4 holds certain clinical value for diagnosing IgAN and suggests its potential role to be a sensitive biomarker and a novel intervention target for IgAN.