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

## TL;DR

This study identifies TNFRSF1A as a key driver of immune changes in diabetic kidney disease using multi-omics data and zebrafish models.

## Contribution

The novel contribution is identifying TNFRSF1A as a causal mediator of immune reprogramming in DKD through multi-omics and genetic evidence.

## Key findings

- TNFRSF1A is enriched in cortical kidney regions and linked to immune cell infiltration patterns in DKD.
- Mendelian Randomization analysis shows TNFRSF1A has a causal association with DKD (OR = 1.78).
- Zebrafish experiments confirm increased TNFRSF1A expression after pdx1 knockdown.

## Abstract

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 (TNFRSF1A) in DKD development. Findings were further validated in zebrafish embryos depleted of pdx1, an established model of DKD. Spatial transcriptomic analysis showed that TNFRSF1A 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 TNFRSF1A (OR = 1.78, 95% CI: 1.17–2.71, p = 0.007) as a gene with genetic evidence supporting a causal association. Consistent with the human data, experiments in zebrafish showed that TNFRSF1A expression increases significantly following pdx1 knockdown (p = 0.0025). Together, these findings support a role for TNFRSF1A in immune microenvironment reprogramming in DKD, while not excluding the involvement of additional regulatory pathways.