Characterization of Aging-Associated Renal Phenotypes in Renal Tubular Cell-Specific NFAT5 Knockout Mice

Background: The number of patients with chronic kidney disease (CKD) and hypertension is increased with age; however, it is not clearly defined why and how aging causes renal dysfunction and hypertension. Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor that is activated upon hypertonic conditions as observed in the renal medulla. Genome-wide association study has suggested that NFAT5 variants are associated with the elevation of blood pressure. We have shown that the renal tubular cell-specific NFAT5 conditional knockout (KO) mice exhibit salt-sensitive hypertension, while the mice exhibit impaired urine concentrating ability and are susceptible to renal fibrosis. These phenotypes resemble aging-associated renal dysfunction, i.e., urine concentrating disorder, salt-sensitive hypertension, and renal fibrosis. We therefore investigated the possible involvement of NFAT5 in aging-related changes of the kidney. Methods: Aged NFAT5 KO mice (18 months old) were characterized in terms of aging-related renal phenotypes and compared with wild type (WT) mice. Kidney function was evaluated by serum creatinine. Gene expressions of senescence-associated secretory phenotype (SASP)-related factors (IL-6, IFNγ, TGF-β1, CDKN1A (p21), CDKN2A (p16), COL1A1, PAI-1, MMP3) were examined by real-time PCR. Renal fibrosis was evaluated by AZAN staining. Results: Gene expressions of SASP-related factors were significantly increased in KO mice compared with WT mice. KO mice exhibited renal atrophy and fibrosis in the medulla. Serum creatinine was significantly higher in KO mice than in WT mice. Conclusion: These results suggest that renal tubular NFAT5 protects against the progression of aging-associated chronic kidney disease.