Network expression analysis identifies and experimentally validates the involvement of Fosb in acute kidney injury

Abstract

Acute kidney injury (AKI) is a complex clinical syndrome associated with increased incidence and mortality rates among critically ill patients, often leading to multiple organ dysfunction, which underscores the need to better understand its molecular mechanisms. In this study, common differentially expressed genes (DEGs) between various AKI models and control groups were extracted using the Gene Expression Omnibus (GEO) database, followed by an exploration of potential signaling pathways involved in AKI. Key genes in the development of AKI were identified through Weighted Gene Co-expression Network Analysis (WGCNA) and protein–protein interaction (PPI) networks, and the expression of hub genes was validated using quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC) and flow cytometry. A total of 1265 DEGs significantly associated with AKI were identified, with GO and KEGG analyses revealing significant enrichment in pathways related to kidney development, muscle regulation, and amino acid biosynthesis. WGCNA further screened AKI-related modules, identifying 290 DEGs significantly linked to the disease state. PPI network analysis revealed Fosb as a significantly upregulated hub gene in AKI, with experimental validation demonstrating its substantial upregulation in patients with acute tubular necrosis (ATN), HR-induced HK-2 cells injury and ischemia–reperfusion injury (IRI) mice. Inhibition of Fosb alleviated hypoxia-reoxygenation (HR)-induced apoptosis and inflammation in HK-2 cells by suppressing the AP-1 complex (Fosb/C-Jun) signaling pathway. Therefore, Fosb is significantly upregulated in AKI and associated with inflammation mediated by the AP-1 signaling pathway, suggesting its potential as a diagnostic biomarker and therapeutic target for AKI.