PS-BPB10-5: POSSIBLE INVOLVEMENT OF RENAL TUBULAR NFAT5 IN AGING-ASSOCIATED RENAL DYSFUNCTION AND SALT-SENSITIVE HYPERTENSION

Abstract

Objective: Japan is currently facing a super-aging society, where an incidence of lifestyle-related diseases has become a greater social burden. The number of patients with chronic kidney disease (CKD) and hypertension is being 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. 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: Male wild-type (WT) and KO mice (12 weeks old) were subjected to unilateral ureteral obstruction (UUO) or sham operation. After 7 days, mice were sacrificed and kidneys were removed for analysis. Renal fibrosis was evaluated by AZAN staining. Senescence-associated beta-galactosidase (SA-β;-Gal) activity was examined by fluorescence study in the whole kidney slices. mRNA expression for senescence-associated secretory phenotype (SASP)-related factors (TGF-β;1, COL1A1, ICAM1, PAI-1, p21, p16, and p53) in the whole kidney tissue was examined by real-time PCR. Results: AZAN staining showed that UUO induced renal fibrosis both in WT and KO mice. The UUO-induced fibrotic area was significantly larger in KO mice than in WT mice in the medulla. In sham-operated mice, overall SA-β;-Gal activity was larger in KO mice, in which the activity was dominant in the corticomedullary region. In UUO groups, overall SA-β;-Gal activity was low compared to sham-operated groups. The mRNA expression of SASP-related factors was not different between WT and KO mice in sham-operated groups. UUO upregulated the mRNA expression of all SASP-related factors both in WT and KO mice. In UUO groups, the expression of TGF-β;1, COL1A1, ICAM1, and PAI-1 was significantly larger in KO mice than in WT mice. The expression of p21, p16, and p53 tended to be larger in KO mice than in WT mice. Conclusions: Renal tubular NFAT5 deficiency showed senescence-related phenotypes at baseline. Deficit of renal tubular NFAT5 may further induce cell senescence upon insult, which might accelerate aging-associated renal inflammation and dysfunction in CKD.