Glucocorticoid signaling promotes salt-sensitive hypertension via induction of SGK1 expression and metabolomic shift in antigen-presenting cells

Salt sensitivity of blood pressure (SSBP) is a condition characterized by elevation in blood pressure following increased dietary salt intake. Additionally, our data have indicated that high sodium intake through ENaC shifts the metabolome of antigen-presenting cells (APCs). ENaC activation and stabilization have frequently been implicated by SGK1 activation. However, the mechanistic interplay between SGK1 expression and excess dietary Na + influx in APCs leading to SSBP and metabolic changes has not yet been elucidated. Medical conditions involving excess cortisol caused by polymorphic mutations in the HSD11B2 gene have been associated with hypertension. Moreover, cortisol has been found to induce SGK1 expression by activating glucocorticoid response elements, and its excess is implicated in mitochondrial dysfunction, which can lead to an altered metabolome. Thus, I hypothesize that glucocorticoid signaling promotes SSBP via induction of SGK1 expression, which is coupled with metabolomic shift and mitochondrial distress. To test this, an in-depth metabolomic analysis was conducted on individuals rigorously characterized for SSBP using a protocol involving inpatient salt-loading and salt-depletion. From this, I demonstrated that glucocorticoid receptor (NS: 5504.36 ± 1369.10; HS: 5915.73 ± 2391.55; q = 0.043) rather than mineralocorticoid receptor (NS: 56.45 ± 16.65; HS: 75.55 ± 38.43; q = 0.85) is transcribed in a parallel manner to SGK1 (NS: 11962.91 ± 5474.72; HS: 11195.45 ± 5504.51; q < 0.0001) in monocytes exposed to high salt, and there is a direct correlation between their changes in expression (r > 0.8; p < 0.01). This investigation also unveiled substantial alterations in cortisol metabolism due to salt loading/depletion, exhibiting a pattern that aligns with hemodynamic shifts corresponding to SSBP (r > 0.7; p < 0.05). We observed this feat particularly in urine but not plasma, and the urinary cortisol-to-cortisone ratio correlated with SSBP (r > 0.6; p < 0.7), and high salt exacerbates these metabolomic changes and induces mitochondrial fragmentation (p < 0.05), which can lead to several other metabolomic changes. Collectively, these data suggest that glucocorticoid signaling in conditions of high salt promotes salt-sensitive hypertension and impacts intracellular metabolomics. This study was supported by several grants between Meharry Medical College, Vanderbilt University, and the University of Pittsburgh. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.