Abstract MP33: Heterozygous Knockout Of Nfatc1 In Mice Is Protective Against Salt-sensitive Hypertension

Abstract

Nuclear Factor of Activated T Cells 1 (NFATC1) plays a role in the immune response and has been shown to be required for cardiac development. A recent trans-ethnic meta-analysis of genome-wide association studies (GWAS) found the NFATC1 gene in humans was associated with estimated glomerular filtration rate (eGFR). Further studies in salt-sensitive mice showed a decrease in renal Nfact1 mRNA expression during high-salt exposure, suggesting a link between NFATC1 and salt-sensitive hypertension. Here, we backcrossed a knockout mouse model of Nfatc1 to a salt-sensitive 129S6 background for 6 generations. Heterozygous (Het) and wild-type (WT) male mice at 8-12 weeks of age were trained for blood pressure measurement by tail cuff manometry over 2 weeks, and measurements were taken over the following week while on standard chow (NSD), and again for 2+1 weeks while on a matched high-salt diet (HSD, 6% total NaCl). On NSD, there was no difference in SBP between WT and Het mice. However, while WT mice displayed an expected elevation in SBP on HSD, Het mice showed no change in SBP, resulting in a statistically significant difference between genotypes (140.7±11.1 mmHg vs 125.7±9.7 mmHg, p = 0.02, n = 8/6). This preliminary data suggests that down-regulation of Nfatc1 under HSD may be a compensatory response to limit the rise in blood pressure during high salt consumption, and that NFATC1 may be a therapeutic target for salt-sensitive hypertension. Further studies are underway to delineate the molecular mechanism by which Nfatc1 mediates salt-sensitivity.