Abstract Body (Do not enter title and authors here): Background: Salt-sensitivity of blood pressure (SSBP) has been shown to correlate with insulin resistance, metabolic syndrome, and cardiovascular mortality. Hypertension can often be seen in settings of obesity, leptin resistance, and insulin resistance, though the exact mechanistic interaction of these conditions has yet to be elucidated. Inhibition of the mammalian target of rapamycin (mTOR), a major regulator of both insulin and leptin pathways, promotes symptoms of metabolic syndrome. We have previously shown high sodium environments activate antigen presenting cells (APCs) towards an inflammatory phenotype contributing to the pathogenesis of SSBP. In this study, we investigated whether in vitro and in vivo high sodium exposure affect leptin and insulin signaling in human monocytes.
Methods: SSBP was assessed using a modified Weinberger salt-loading and depletion protocol (age was 49.25±1.98, 80% male, screening SBP/DBP was 137.3±4/88.2±2.9). Single cell sequencing was performed on circulating immune cells. In additional experiments, bulk RNA sequencing was performed on monocytes isolated from 11 healthy individuals and were treated in vitro with either normal sodium (150mM) or high sodium(190mM). We analyzed the RNA sequence data and cross-referenced these results with a comprehensive list of genes associated with insulin and leptin signaling using the NIH Gene database and the Harmonizome 3.0 database from Ma’ayan laboratory at Icahn School of Medicine. Pearson correlation was used to analyze the associations. Salt sensitivity index (SSI) is the difference in SL versus SD systolic blood pressure.
Results: We found an overall downregulation of both insulin and leptin signaling genes. Of note, there was a significant downregulation of genes for leptin (log2FC=-2.5; padj<0.0001), leptin receptor (log2FC=-0.53; padj=0.002), insulin receptor (log2FC=-0.36, padj=0.007), and glucose transporter 1 (log2FC=-0.74; padj=0.001). Although mTOR was not significant (log2FC=-0.07; padj=0.69), proline-rich AKT1 substrate 1, a direct inhibitor of mTOR activity, (log2FC=0.71; padj<0.001), was significantly upregulated. Furthermore, we found an inverse correlation between DAKT1S1 and SSI (r=-0.93; p=0.008).
Conclusions: Our findings suggest that high salt exposed monocytes have impaired leptin and insulin signaling, which may be a factor to promote insulin and leptin resistance contributing to the development of metabolic syndrome in salt-sensitive hypertension.