NFIC transcriptionally activates DUSP1 to attenuate high glucose-induced mesangial cell injury in diabetic nephropathy: insights from integrative transcriptomics and functional studies

Background Diabetic nephropathy (DN) is characterized by mesangial cell (MC) injury, extracellular matrix (ECM) deposition, and inflammatory imbalance, yet the upstream transcriptional mechanisms remain poorly understood. Objectives This study aimed to dissect transcriptomic features of DN MCs and elucidate key regulatory axes through integrative transcriptomics and functional validation. Methods GSE96804 and GSE209781 datasets were integrated to identify differentially expressed genes (DEGs) common to DN glomeruli and MCs. Intersecting DEGs were subjected to GO and KEGG enrichment analyses. Core transcription factors and downstream effectors were identified using transcription factor (TF) enrichment analysis and random forest machine learning. In high glucose (HG)-induced MCs, overexpression, ChIP-qPCR, dual-luciferase reporter, and functional rescue experiments were performed to validate regulatory mechanisms and effects on cell injury. Results Integrative transcriptomics identified 63 genes commonly dysregulated in DN glomeruli and MCs. Transcription factor enrichment revealed nuclear factor I/C (NFIC) as a key upstream regulator, significantly downregulated in DN. Dual-specificity phosphatase 1 (DUSP1) was identified as the core downstream effector, showing strong positive correlation with NFIC ( r = 0.746, P < 0.001). Mechanistically, NFIC directly bound to the DUSP1 promoter to initiate its transcription, and HG-induced DUSP1 downregulation was reversed by NFIC overexpression. Functionally, NFIC overexpression attenuated HG-induced ECM deposition, oxidative stress, and inflammatory responses. DUSP1 silencing reversed these protective effects, confirming DUSP1 as a key downstream mediator. Conclusion NFIC inhibits HG-induced MC injury by directly activating DUSP1 transcription, thereby suppressing ECM deposition, oxidative stress, and inflammation.