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

A sodium-HIF1α axis coordinates immune metabolic reprogramming and mitochondrial remodeling in salt-sensitive hypertension | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A sodium-HIF1α axis coordinates immune metabolic reprogramming and mitochondrial remodeling in salt-sensitive hypertension Ronald McMillan, Selam Desta, Jeremiah Afolabi, Ariel Thorson, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9504540/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Molecular Biology Immunology Cardiac & Cardiovascular Systems Hypoxia Inducible Factor 1 Alpha metabolic reprogramming antigen-presenting cells glycolysis hypertension Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9504540","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628275128,"identity":"deab2a2c-ab17-4494-a194-2fc76f672a37","order_by":0,"name":"Ronald McMillan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYLCCB2wgkrHxwAMGBjnitCRAtDQcSGBgMCZFCwMDSEtiAyHV5u29Bz8klDFE8087DLSl5k76hhvZiR8YKu7Z4dIrc+ZcskTCOYbcGbcTgVqOPcvdcCN3swTDmeJkXFokJHIMJBLbGHI3SIO0sB3OnTkjdxsDY1tCMi6HAbUY/0Bo+Xc4XZIILWYIWxLbDifwS0C02OHUwnPGzCLhnATEL4l9hw37ed5ulkg4k5CAUwt7j/GND2U2uf2z0x8++PDtsDwbe+7GDx8qEuxxaYHpROMnEBNBGICQLaNgFIyCUTByAACkgl5XZOYP6AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8363-8805","institution":"Vanderbilt University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Ronald","middleName":"","lastName":"McMillan","suffix":""},{"id":628275129,"identity":"8e304d04-377e-48d2-b88b-11ae1c30dd8f","order_by":1,"name":"Selam Desta","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Selam","middleName":"","lastName":"Desta","suffix":""},{"id":628275130,"identity":"b60dffeb-35f7-481b-b8a4-cf8c3758c8e2","order_by":2,"name":"Jeremiah Afolabi","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeremiah","middleName":"","lastName":"Afolabi","suffix":""},{"id":628275131,"identity":"5a8cebd6-fa32-4941-bc91-d8edd9498a12","order_by":3,"name":"Ariel Thorson","email":"","orcid":"","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Ariel","middleName":"","lastName":"Thorson","suffix":""},{"id":628275132,"identity":"925ec332-346d-449f-8b4a-8f7cba965739","order_by":4,"name":"Olivia Pierre-Louis","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Olivia","middleName":"","lastName":"Pierre-Louis","suffix":""},{"id":628275133,"identity":"040ac0d6-0134-4ae8-b106-7def83b5dc98","order_by":5,"name":"Ashley Mutchler","email":"","orcid":"","institution":"Meharry medical college","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"","lastName":"Mutchler","suffix":""},{"id":628275134,"identity":"6af99d76-2ac2-49be-a347-d26d641cb656","order_by":6,"name":"Joyanna Gamble-George","email":"","orcid":"https://orcid.org/0000-0002-5492-9216","institution":"Johns Hopkins University","correspondingAuthor":false,"prefix":"","firstName":"Joyanna","middleName":"","lastName":"Gamble-George","suffix":""},{"id":628275135,"identity":"582cd623-870e-4e01-8013-dfb171189b50","order_by":7,"name":"Prasanna Katti","email":"","orcid":"","institution":"Indian Institute of Science Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Prasanna","middleName":"","lastName":"Katti","suffix":""},{"id":628275136,"identity":"11eb9b5b-29f9-4c15-8ae9-7949c73c9a21","order_by":8,"name":"Suraj Thapliyal","email":"","orcid":"","institution":"Indian Institute of Science Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Suraj","middleName":"","lastName":"Thapliyal","suffix":""},{"id":628275137,"identity":"a01af272-13a7-4811-bdfe-0f8205c92095","order_by":9,"name":"Mohammad Saleem","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Saleem","suffix":""},{"id":628275138,"identity":"b50b8c46-3f6d-48b0-b16c-34a2d3ecd854","order_by":10,"name":"Mert Demirci","email":"","orcid":"","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Mert","middleName":"","lastName":"Demirci","suffix":""},{"id":628275139,"identity":"bce0767d-13d1-43dd-b972-f5d0e51efaab","order_by":11,"name":"Lale A. 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