Abstract Body: Background: Nuclear factor of activated T cells-cytoplasmic 1 (NFATc1) has recently been shown to have a non-canonical role in chronic kidney disease in humans by a trans-ethnic meta-analysis of genome-wide associate studies (GWAS). Follow-up studies in a salt-sensitive mouse model showed that Nfatc1 mRNA expression was suppressed in the kidneys when animals were fed a high-salt diet. Here, we further explore the link between NFATc1 and salt-sensitive (SS) hypertension.

Methods: Adult male wild-type (WT) and heterozygous Nfatc1 knockout (Het) mice (2-5 months of age) on the SS 129S6 background were started on standard chow (0.8% NaCl, NSD) and then switched to a high-salt diet (6% NaCl, HSD). Systolic blood pressure (SBP) was measured by either tail cuff manometry with at least 2 weeks of training or implantable radiotelemetry transmitters with at least 2 weeks of post-surgical recovery. Immediately before and for 2-3 days after the change in diet, 24 h urine was collected using metabolic cages, and urinary sodium was measured by flame photometry. Sigmoid pressure-natriuresis curves were generated and the Hill slope was compared between genotypes.

Results: WT mice showed a significant increase in SBP between NSD and after 3 weeks on HSD (127.8±9.9 vs 143.4±8.9, p = 0.0089, n = 9). In contrast, Het mice had no change in SBP (125.8±8.7 mmHg vs. 125.7±10.6 mmHg, p = 1.0, n = 9). During the initial switch to the HSD, SBP was not significantly different between WT and Het mice (133.2±2.9 vs. 134.4±3.0, p = 0.45, n = 7/group). However, WT mice had a shallower pressure-natriuresis curve (Hill slope of 0.58 vs. 0.93, 7 mice/group, 25/26 data points).

Conclusion: Our data illustrates that decreasing Nfatc1 expression in a mouse model is protective against SS hypertension. While acute increases in SBP in response to HSD remained in Het mice, sodium excretion was increased and SBP remained unchanged after 3 weeks, indicating that NFATc1 has the potential to be a therapeutic target against SS hypertension.