Abstract Body: Salt sensitivity of blood pressure, characterized by blood pressure fluctuations that
mirror dietary sodium (Na) intake, is an independent risk factor for cardiovascular
morbidity and mortality in people with and without hypertension. We previously found
that elevated Na uptake via the amiloride-sensitive epithelial sodium channel (ENaC) in
antigen-presenting cells leads to the upregulation of isolevuglandins and
proinflammatory cytokines ultimately leading to T cell activation and salt-sensitive
hypertension. In addition, we also showed that SMAD3 activation plays a role in
inflammation and salt-sensitive hypertension. In previous studies, RGMa has been
shown to be upstream of SMAD3. Furthermore, previous studies have also shown that
knockdown of RGMa leads to reduced levels of TGFβ1-induced SMAD3
phosphorylation. The exact mechanism by which elevated extracellular Na leads to
increased blood pressure remains unknown. We hypothesized that RGMa complexes
with TGFβ1R1 to promote SMAD3 phosphorylation ultimately contributing to
inflammation in salt-sensitive hypertension. To test our hypothesis, we isolated
monocytes from human participants (N =11) and treated them with either high (190
mMol/L) or normal (150 mMol/L) Na in vitro for 72 hours and subsequently performed
bulk RNA sequencing. In additional experiments, we performed an in vivo high Na
treatment by utilizing a rigorous salt-loading/depletion protocol on human participants (N
= 9) and conducted single-cell transcriptomic analyses. Our bulk RNA sequencing
analyses revealed there was no difference in expression of TGFβ1R1 (8837 ± 780.9 vs.
9688 ± 942.5, p =0.350) and TGFβ1R2 (7012 ± 717.0 vs. 7176 ± 633.9, p = 0.059).
Interestingly, RGMa (2253 ± 441.0 vs. 516 ± 84.1, p <0.001) and TGFβ1 (5118 ± 353.9
vs. 9067 ± 826.4, p = 0.073) were significantly upregulated in human monocytes after
high Na treatment compared to normal salt. However, single-cell transcriptomic
analyses found no correlation between the changes in pulse pressure and RGMa (r =
0.5154, p = 0.1911). Our data suggest that RGMa mediates Na-induced inflammation
but may not play a role in salt-sensitive hypertension.