{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:53:10Z","timestamp":1792896790985,"version":"4.5.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>The risk of heart failure (HF) is significantly higher in patients with type 2 diabetes mellitus (T2DM). Recent studies have shown that an imbalance in the sympathetic nervous system (SNS) is a target for sodium-glucose cotransporter-2 inhibitors (SGLT-2i), which have been proven to reduce the risk of adverse HF outcomes in several clinical trials. However, the specific central mechanisms involved remain unclear. Therefore, our research investigates how dapagliflozin (DAPA) regulates blood pressure through SNS and explores the central neural and endocrinological pathways by which DAPA, an SGLT-2i, influences SNS activity and its impact on the cardiovascular system in the treatment of HF in T2DM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Material and methods<\/jats:title>\n                    <jats:p>Twenty-one male C57BL\/6 mice aged 8\u201310 weeks were randomly divided into three groups (n = 7 each): control (CTRL), DAPA, and DAPA-Cyanine 3 (DAPA-Cy3). Blood pressure (BP), heart rate (HR), and blood glucose (BG) were measured after a single dose of treatment. DAPA-Cy3 was designed to assess its ability to cross the blood-brain barrier (BBB). Additionally, histological co-localization analyses of immunoreactivity for c-Fos, neuronal nitric oxide synthase (nNOS), corticotropin-releasing hormone (CRH), and vasopressin (VP) across groups were performed to explore how SGLT-2 inhibitors regulate the central sympathetic nervous system (SNS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>1) DAPA significantly reduced both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in mice, without notably affecting the heart rate (HR); 2) SGLT-2 was found to be extensively expressed in the central nervous system (CNS), especially in the hypothalamus and brainstem; 3) DAPA-Cy3 was able to cross the blood-brain barrier (BBB) and disperse throughout the brain; and 4) DAPA clearly influenced the activity of specific neurons expressing nNOS, CRH, and VP in the hypothalamus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DAPA, as an SGLT-2 inhibitor, crosses the BBB and binds to the innate SGLT-2 in the hypothalamus and brainstem of mice. This significantly influences the tone of the SNS through indirect regulation by modulating nNOS, CRH, and VP, which are believed to be the upstream regulatory points of SGLT-2 in interacting with the SNS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1689167","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T06:48:25Z","timestamp":1769150905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dapagliflozin lowers blood pressure via regulating the sympathetic neural activity in the paraventricular nucleus of hypothalamus in normal mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Meiyuan","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Shanghai Pudong Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shanghai Pudong Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ligang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shanghai Pudong Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shanghai Pudong Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Fudan Zhangjiang Institute, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2014.08.004","article-title":"Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure","volume":"3","author":"Dei Cas","year":"2015","journal-title":"JACC: Heart Failure"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.15420\/cfr.2016:20:2","article-title":"Heart failure in patients with diabetes mellitus","volume":"3","author":"Rosano","year":"2017","journal-title":"Card Fail Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.163","article-title":"Neurohormonal activation in heart failure with reduced ejection fraction","volume":"14","author":"Hartupee","year":"2017","journal-title":"Nat Rev Cardiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.bmb.a070481","article-title":"Hypothalamic regulation of the cardiovascular system","volume":"22","author":"Hilton","year":"1966","journal-title":"Br Med Bull"},{"key":"B5","doi-asserted-by":"publisher","first-page":"8917578","DOI":"10.1155\/2016\/8917578","article-title":"Update on RAAS modulation for the treatment of diabetic cardiovascular disease","volume":"2016","author":"Bernardi","year":"2016","journal-title":"J Diabetes Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"100192","DOI":"10.1016\/j.ynstr.2019.100192","article-title":"CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses","volume":"11","author":"Jiang","year":"2019","journal-title":"Neurobiol Stress"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2174\/156720213804805963","article-title":"Neuronal nitric oxide synthase and sympathetic nerve activity in neurovascular and metabolic systems","volume":"10","author":"Wang","year":"2013","journal-title":"Curr neurovascular Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00330.2011","article-title":"Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure","volume":"301","author":"Zheng","year":"2011","journal-title":"Am J Physiol Heart Circulatory Physiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1982.tb37490.x","article-title":"Vasopressin projections and central control of cardiovascular function","volume":"394","author":"Berecek","year":"1982","journal-title":"Ann New York Acad Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11906-018-0811-0","article-title":"Vasopressin, central autonomic control and blood pressure regulation","volume":"20","author":"Lozic","year":"2018","journal-title":"Curr Hypertens Rep"},{"key":"B11","first-page":"47","article-title":"Role of paraventricular nucleus vasopressin V1A receptors in the response to endothelin 1 activation of the subfornical organ in the rat","author":"Rossi","year":"2008","journal-title":"J Physiol Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2016.10.024","article-title":"Over-expression of V1A receptors in PVN modulates autonomic cardiovascular control","volume":"114","author":"Lozi\u0107","year":"2016","journal-title":"Pharmacol Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3180","article-title":"SGLT2 inhibition \u2014 a novel strategy for diabetes treatment","volume":"9","author":"Chao","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"B14","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nrendo.2011.243","article-title":"SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects","volume":"8","author":"Ferrannini","year":"2012","journal-title":"Nat Rev Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s11892-018-1011-7","article-title":"Molecular mechanisms underlying the cardiovascular benefits of SGLT2i and GLP-1RA","volume":"18","author":"Khat","year":"2018","journal-title":"Curr Diabetes Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32590-X","article-title":"SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials","volume":"393","author":"Zelniker","year":"2019","journal-title":"Lancet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.26313","article-title":"A systematic review of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sympathetic nervous system inhibition: an underrated mechanism of cardiorenal protection","volume":"14","author":"Raza","year":"2022","journal-title":"Cureus"},{"key":"B18","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s11906-022-01170-z","article-title":"Targeting features of the metabolic syndrome through sympatholytic effects of SGLT2 inhibition","volume":"24","author":"Herat","year":"2022","journal-title":"Curr Hypertens Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19177","article-title":"Dapagliflozin attenuates sympathetic and pressor responses to stress in young prehypertensive spontaneously hypertensive rats","volume":"79","author":"Kim","year":"2022","journal-title":"Hypertension"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-17-0263","article-title":"Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice","volume":"234","author":"Millar","year":"2017","journal-title":"J Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S258593","article-title":"Dapagliflozin activates neurons in the central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice","volume":"13","author":"Nguyen","year":"2020","journal-title":"Diabetes Metab Syndr Obes"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15030883","article-title":"Modification of the linker amino acid in the cell-penetrating peptide nickFect55 leads to enhanced pDNA transfection for in vivo applications","volume":"15","author":"H\u00e4rk","year":"2023","journal-title":"Pharmaceutics"},{"key":"B23","doi-asserted-by":"crossref","DOI":"10.1017\/S0016672300028548","article-title":"Antibodies: A laboratory manual. Edited by Ed Harlow and David Lane. Cold Spring Harbor: cold spring harbor laboratory. New York. 1988. 726 pages. Paper $50.00. ISBN 0 87969 314 2","volume":"54","author":"Ridley","year":"1989","journal-title":"Genetical Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1038\/s41467-025-57788-5","article-title":"Cortico-striatal circuit mechanisms drive the effects of D1 dopamine agonists on memory capacity in mice through cAMP\/PKA signalling","volume":"16","author":"De Risi","year":"2025","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.84262.sa2","article-title":"Multimodal mapping of cell types and projections in the central nucleus of the amygdala","volume":"12","author":"Wang","year":"2023","journal-title":"Elife"},{"key":"B26","first-page":"620","article-title":"The design of experiments: Statistical principles for practical applications","volume-title":"The design of experiments: Statistical principles for practical applications","year":""},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2017.04.010","article-title":"Diabetes mellitus and heart failure","volume":"130","author":"Lehrke","year":"2017","journal-title":"Am J Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in patients with heart failure and reduced ejection fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N Engl J Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab887","article-title":"The year in cardiovascular medicine 2021: heart failure and cardiomyopathies","volume":"43","author":"Bauersachs","year":"2022","journal-title":"Eur Heart J"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jdiacomp.2015.10.012","article-title":"EMPA-REG \u2013 the \u201cdiuretic hypothesis","volume":"30","author":"McMurray","year":"2016","journal-title":"J Diabetes its Complications"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12500","article-title":"Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels","volume":"17","author":"Sj\u00f6str\u00f6m","year":"2015","journal-title":"Diabetes Obes Metab"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-025-02216-w","article-title":"Interaction between SGLT2 and the sympathetic nervous system in normal and various cardiovascular metabolic disease states","volume":"48","author":"Katsurada","year":"2025","journal-title":"Hypertens Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12572","article-title":"Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes","volume":"17","author":"Chilton","year":"2015","journal-title":"Diabetes Obes Metab"},{"key":"B34","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1007\/s11886-019-1165-1","article-title":"Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure","volume":"21","author":"Scheen","year":"2019","journal-title":"Curr Cardiol Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jash.2017.07.005","article-title":"The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus","volume":"11","author":"Jordan","year":"2017","journal-title":"J Am Soc Hypertension"},{"key":"B36","doi-asserted-by":"publisher","first-page":"393","DOI":"10.2147\/VHRM.S111991","article-title":"Impact of sodium-glucose cotransporter 2 inhibitors on blood pressure","volume":"12","author":"Reed","year":"2016","journal-title":"Vasc Health Risk Manage"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11886-018-0943-5","article-title":"SGLT2 inhibitors and mechanisms of hypertension","volume":"20","author":"Briasoulis","year":"2018","journal-title":"Curr Cardiol Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S399367","article-title":"The neuronal and non-neuronal pathways of sodium-glucose cotransporter-2 inhibitor on body weight-loss and insulin resistance","volume":"16","author":"Dong","year":"2023","journal-title":"Diabetes Metab syndrome obesity: Targets Ther"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00421","article-title":"The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity","volume":"9","author":"Wan","year":"2018","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s13300-010-0006-4","article-title":"Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members","volume":"1","author":"Chen","year":"2010","journal-title":"Diabetes Ther"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2020.09.008","article-title":"Potential therapeutic effects of sodium glucose-linked cotransporter 2 inhibitors in stroke","volume":"42","author":"Al Hamed","year":"2020","journal-title":"Clin Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00317.2012","article-title":"Regional distribution of SGLT activity in rat brain","volume":"304","author":"Yu","year":"2013","journal-title":"vivo. Am J Physiol Cell Physiol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016050510","article-title":"Dapagliflozin binds specifically to sodium-Glucose cotransporter 2 in the proximal renal tubule","volume":"28","author":"Ghezzi","year":"2017","journal-title":"J Am Soc Nephrology: JASN"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26237213","article-title":"Neuroprotective effect of SGLT2 inhibitors","volume":"26","author":"Pawlos","year":"2021","journal-title":"Molecules"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-018-0316-5","article-title":"Impaired hypothalamic regulation of sympathetic outflow in primary hypertension","volume":"35","author":"Zhou","year":"2019","journal-title":"Neurosci Bull"},{"key":"B46","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.autneu.2016.09.018","article-title":"Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease","volume":"204","author":"Nishihara","year":"2017","journal-title":"Auton Neurosci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/347768a0","article-title":"Localization of nitric oxide synthase indicating a neural role for nitric oxide","volume":"347","author":"Bredt","year":"1990","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-022-01187-4","article-title":"A critical role for the paraventricular nucleus of the hypothalamus in the regulation of the volume reflex in normal and various cardiovascular disease states","volume":"24","author":"Zheng","year":"2022","journal-title":"Curr Hypertens Rep"},{"key":"B49","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.niox.2019.03.005","article-title":"Exercise training augments neuronal nitric oxide synthase dimerization in the paraventricular nucleus of rats with chronic heart failure","volume":"87","author":"Sharma","year":"2019","journal-title":"Nitric Oxide"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1099-4","article-title":"Brain glucose-sensing mechanism and energy homeostasis","volume":"56","author":"Lopez-Gambero","year":"2019","journal-title":"Mol Neurobiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2834","article-title":"Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease","volume":"11","author":"Luscher","year":"2010","journal-title":"Nat Rev Neurosci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10124","article-title":"Paraventricular nucleus of the human hypothalamus in primary hypertension: activation of corticotropin-releasing hormone neurons","volume":"443","author":"Goncharuk","year":"2002","journal-title":"J Comp Neurol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1161\/HYPERTENSIONAHA.118.11497","article-title":"CRHR2 (Corticotropin-releasing hormone receptor 2) in the nucleus of the solitary tract contributes to intermittent hypoxia-induced hypertension","volume":"72","author":"Wang","year":"2018","journal-title":"Hypertension"},{"key":"B54","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.tins.2009.11.004","article-title":"Osmosensation in vasopressin neurons: changing actin density to optimize function","volume":"33","author":"Prager-Khoutorsky","year":"2010","journal-title":"Trends Neurosci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00312.2015","article-title":"Salt-induced sympathoexcitation involves vasopressin V1a receptor activation in the paraventricular nucleus of the hypothalamus","volume":"309","author":"Ribeiro","year":"2015","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1111\/jne.12051","article-title":"Physiological regulation of magnocellular neurosecretory cell activity: integration of intrinsic, local and afferent mechanisms","volume":"25","author":"Brown","year":"2013","journal-title":"J Neuroendocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1689167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T06:48:26Z","timestamp":1769150906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1689167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":56,"alternative-id":["10.3389\/fendo.2026.1689167"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1689167","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,23]]},"article-number":"1689167"}}