Dual inhibition of SGLT 1 and 2 by sotagliflozin alleviates intracellular sodium overload and improves cardiometabolic remodelling in uraemic cardiomyopathy
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ID: 324714
2026
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Abstract
AIMS: Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD. METHODS AND RESULTS: CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins. CONCLUSION: Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.
| Reference Key |
openalex_W7202209086
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| Authors | Megan Young, Anja Karlstaedt, Sanushi Dambure, Jack J J J Miller, Tong Guo, Xin Zhou, Zenouska Ramchunder, Jair Marques, Muriel Nobles, Andrew Tinker, Kyuongmin Kim, Amanda R Purcell, Sarah J. Glastras, Fenn Cullen, Thomas R. Eykyn, Alex von Kriegsheim, Blanca Rodríguez, Michelangelo Campanella, Michael J. Shattock, Nay Aung, Claudia P Cabrera, Magdi Yaqoob, Dunja Aksentijević |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag167
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| URL | |
| Keywords | Keywords not found |
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