Multi-Omics Integration Identifies TNFRSF1A as a Causal Mediator of Immune Microenvironment Reprogramming in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. However, the inflammatory mediators that causally drive disease progression remain incompletely defined. In this study, we used a multi-omics approach that combined single-cell RNA sequencing, spatial transcriptomics, pseudotime trajectory analysis, cell-to-cell communication analysis, and Mendelian randomization (MR) to investigate the role of tumor necrosis factor receptor superfamily member 1A (<i>TNFRSF1A</i>) in DKD development. Findings were further validated in zebrafish embryos depleted of <i>pdx1</i>, an established model of DKD. Spatial transcriptomic analysis showed that <i>TNFRSF1A</i> is enriched in cortical kidney regions. Pseudotime analysis revealed progressive immune reprogramming, with an early predominance of T and NK cells and gradual shift to myeloid infiltration and B-cell expansion. Cell-to-cell communication analysis highlighted IL-1β and related signaling pathways that increase NF-κB activity. Mendelian Randomization analysis, complemented by PPI network mapping, identified <i>TNFRSF1A</i> (OR = 1.78, 95% CI: 1.17-2.71, <i>p</i> = 0.007) as a gene with genetic evidence supporting a causal association. Consistent with the human data, experiments in zebrafish showed that <i>TNFRSF1A</i> expression increases significantly following <i>pdx1</i> knockdown (<i>p</i> = 0.0025). Together, these findings support a role for <i>TNFRSF1A</i> in immune microenvironment reprogramming in DKD, while not excluding the involvement of additional regulatory pathways.