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bioRxiv · 10.1101/2025.11.18.689108

NFAT5 Confers Differential Expression in Innate Immune Cells vs. Renal Epithelial Cells in the Face of Osmotic Stress

Kraus, X.·Nnah, F.·Cowley, C.·Araos, P.·Wynne, B. M.
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Abstract

The kidney develops an osmotic gradient, up to 1300 mOsm, to drive the reabsorption of water. However, this creates a harsh environment for renal epithelial and immune cells. These cells need to develop a survival mechanism to prevent against osmotic stress and maintain homeostasis in this harsh environment. Nuclear Factor of Activated T Cells 5 (NFAT5, also known as Tonicity-Responsive Enhancer-Binding Protein factor or TonEBP) is a master transcription factor that responds to changes in osmolarity, regulating the transcription of genes that control the intracellular accumulation of osmolytes. Studies suggest that NFAT5 may be responsible for cell survival in this environment. Both epithelial and immune cells play a role in pro-inflammatory responses and disease progression. Additionally, NFAT5 may also play divergent roles, promoting the expression of pro-inflammatory genes in immune cells, and anti-inflammatory genes in epithelial cells. We hypothesized that NFAT5 expression was protective in epithelial cells, while stimulation in immune cells may be proinflammatory. We performed survival assays to assess an NFAT5-dependent role in hyperosmolar environments. We also assessed gene expression and identified targets that may be responsible for cell survival, as well as demonstrating divergent mechanisms in epithelial and immune cells. In conclusion, we found NFAT5 is critical to cell survival in hyperosmolar environments and identified transcripts such as bgt1, aqp1 and akr1b3 that may explain the difference in survival. We also observed a difference in expression between epithelial and raw cells, including the same targets thought to protect against hyperosmotic stress in IMCD3 cells that showed differential regulation by NFAT5. These data suggest a divergent NFAT5 mechanism in two cell types present in the kidney.

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Kraus, X., Nnah, F., Cowley, C., Araos, P., Wynne, B. M.. 2025-11-18. NFAT5 Confers Differential Expression in Innate Immune Cells vs. Renal Epithelial Cells in the Face of Osmotic Stress. https://doi.org/10.1101/2025.11.18.689108

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