Characterization of gene expression in the kidney of renal tubular cell-specific NFAT5 knockout mice

Nuclear factor of activated T-cells 5 (NFAT5, also called TonEBP/OREBP) is a transcription factor that is activated by hypertonicity and induces osmoprotective genes to protect cells against hypertonic condition. In the kidney, renal tubular NFAT5 is known to be involved in the urine concentration mechanism. Previous studies have suggested that NFAT5 modulates the immune system and exerts various effects on organ damages, depending on organ and disease states. Pathophysiological roles of NFAT5 in renal tubular cells, however, still remain obscure. We examined comprehensive analysis by performing transcription start site-sequencing (TSS-Seq) on the kidney of inducible and renal tubular cell-specific NFAT5 knockout (KO) mice. The mice were subjected to unilateral ureteral obstruction (UUO) to examine the relevance of renal tubular NFAT5 in renal fibrosis. The TSS-Seq analysis identified 722 down-regulated and 1,360 up-regulated TSSs, which were differentially regulated ≤ -1.0 and ≥ 1.0 in log2 fold, respectively. Those TSSs were annotated to 532 down-regulated genes and 944 up-regulated genes, respectively. Motif analysis showed that sequences that possibly bind to NFAT5 were enriched in TSSs of down-regulated genes. Gene ontology analysis with the up-regulated genes suggested the disorder of innate and adaptive immune systems in the kidney. UUO significantly exacerbated renal fibrosis in the renal medulla in KO mice compared to WT mice, accompanied by enhanced activation of immune responses. In conclusion, NFAT5 in renal tubules could have pathophysiological roles in renal fibrosis through modulating innate and adaptive immune systems in the kidney.