A sodium-HIF1α axis coordinates immune metabolic reprogramming and mitochondrial remodeling in salt-sensitive hypertension

  • Res Sq. 2026 Apr 24:rs.3.rs-9504540. doi: 10.21203/rs.3.rs-9504540/v1.
Ronald McMillan  1  2  3 ,  Selam Desta  1 ,  Jeremiah Afolabi  1 ,  Ariel Thorson  3 ,  Olivia Pierre-Louis  1 ,  Ashley Mutchler  4 ,  Joyanna Gamble-George  5  6  7 ,  Prasanna Katti  8 ,  Suraj Thapliyal  8 ,  Mohammad Saleem  1 ,  Mert Demirci  9 ,  Lale A Ertuglu  9 ,  Sergey Dikalov  1 ,  Alexandria Porcia Haynes  3 ,  Andrea Marshall  3 ,  Mohd Khan  3 ,  Jenny Schafer  10 ,  Oleg Kovtun  11 ,  Justin Van Beusecum  12  13 ,  Max Kushner  9 ,  Sharia Yasmin  1 ,  Cheryl L Laffer  1 ,  Thomas R Kleyman  14 ,  Celestine Wanjalla  2  15  16 ,  Jeanne A Ishimwe  1 ,  Sydney Jamison  1 ,  Quanhu Sheng  16 ,  Antentor Hinton Jr  3 ,  Annet Kirabo  1  3  15  17  18
Affiliations
  • 1. Department of Medicine, Division of Genetic Medicine Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2. Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3. Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA.
  • 4. Biomedical Sciences, Meharry Medical College, Nashville, TN, USA.
  • 5. Department of Computer Science, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD.
  • 6. Department of Social and Behavioral Sciences, Yale School of Public Health, New Haven, CT.
  • 7. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
  • 8. Department of Biology, Indian Institute of Science Education and Research (IISER), Tirupati, AP, India.
  • 9. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 10. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • 11. Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
  • 12. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
  • 13. Ralph H. Johnson Veterans Affairs Healthcare System, Charleston, South Carolina, USA.
  • 14. Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 15. Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University, Nashville, TN, USA.
  • 16. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 17. Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN, USA.
  • 18. Vanderbilt Institute for Global Health, Vanderbilt University, Nashville, TN, USA.
PMID: 42078875 DOI: 10.21203/rs.3.rs-9504540/v1
Abstract

Salt-sensitivity of blood pressure (SSBP) is associated with immune-metabolic dysfunction, yet the mechanism that coordinates sodium exposure, mitochondrial remodeling, and blood pressure response remains undefined. Phenome-wide and laboratory-value association studies (PheWAS and LabWAS) in the All of Us Research Program identified fluid, electrolyte, and acid-base balance disorders and renal phenotypes as the strongest disease associations. At the same time, hypertension was linked to reduced serum potassium, chloride, and EGFR, corroborating the centrality of renal-electrolyte physiology in blood pressure regulation. Using a within-subject sodium challenge in humans, we show that sodium loading reorganizes circulating tricarboxylic acid (TCA) cycle intermediates in proportion to the individual blood pressure response. Transcriptomic profiling of immune cells under high sodium revealed suppression of Oxidative Phosphorylation, induction of HIF1α-dependent glycolytic gene networks, and rebalancing of the pyruvate dehydrogenase complex. Single-cell chromatin accessibility profiling demonstrated that HIF1α motif activity in circulating immune cells correlates with changes in systolic blood pressure and pulse pressure in salt-sensitive individuals. High sodium induced mitochondrial fragmentation with increased organelle mass and glycolytic capacity. Pharmacological HIF1α inhibition reversed fragmentation while only partially normalizing metabolic output, indicating structural and metabolic remodeling are partially dissociable downstream of HIF1α. Renal HIF1α gain-of-function in mice recapitulated the glycolytic transcriptional response with medullary specificity. Concordantly, Drosophila melanogaster subjected to a high-salt diet exhibited impaired locomotor performance, mitochondrial dysmorphology, intestinal barrier disruption, and cardiac remodeling, establishing evolutionary conservation of sodium-induced end-organ dysfunction independent of an adaptive immune system. Together, these findings identify a HIF1α-dependent axis of mitochondrial metabolic adaptation providing a mechanistic basis for SSBP.

Keywords
Hypoxia Inducible Factor 1 Alpha; antigen-presenting cells; glycolysis; hypertension; metabolic reprogramming.
Products