Abstract P398: Reduced Expression Of Nfatc1 Protects Against Salt-sensitive Hypertension In Mice

Abstract

Background: While nuclear factor of activated T cells-cytoplasmic 1 (NFATc1) is a transcription factor that canonically plays a role in the immune response, it is also widely expressed in non-immune cells. A recent trans-ethnic meta-analysis of genome-wide association studies (GWAS) found that the NFATC1 gene in humans was associated with chronic kidney disease. Additionally, renal Nfact1 mRNA expression was decreased during high-salt exposure in a salt-sensitive murine model, suggesting a link between NFATc1 and salt-sensitive hypertension. Methods: Here, young adult heterozygous Nfatc1 knockout mice (Het) and wild-type (WT) male mice on a salt-sensitive 129S6 background were studied. Systolic blood pressure (SBP) measurements were obtained by either tail cuff manometry with at least 2 weeks of training or implanted radiotelemetry with at least 2 weeks of recovery following surgery. SBP was recorded on standard chow (NSD), on a matched high-salt diet (HSD, 6% total NaCl), or on standard chow with 1000 ng/kg/min angiotensin II (AngII) delivered by osmotic minipump. Pressure natriuresis was examined by correlating 24 h SBP from telemetry with 24 h urine sodium collected in metabolic cages before and for 3 days after switching from NSD to HSD. Results: On NSD, there was no difference in SBP between WT and Het mice (127.8±9.9 vs 125.8±8.7 mmHg, n = 9/group). However, while WT mice displayed an expected elevation in SBP after 3 weeks on HSD, Het mice showed no change in SBP, resulting in a statistically significant difference between genotypes (143.4±8.9 vs 125.7±10.6 mmHg, p = 0.0024, n = 9/group). Pressure natriuresis curves were not significantly different between genotypes. SBP was not significantly different on AngII (167.6±22.2 vs 161.8±10.9 mmHg, n = 2/3). Conclusion: Our preliminary data shows that decreased Nfatc1 expression protects against salt-sensitive hypertension. However, this effect is not mediated through a change in pressure natriuresis, suggesting possible involvement of a vascular mechanism. NFATc1 is a potential therapeutic target in salt-sensitive hypertension.