Sotagliflozin prevents acute kidney injury by suppressing oxidative stress, inflammation, and apoptosis in renal ischemia/reperfusion rat model
DOI:
https://doi.org/10.15584/ejcem.2025.4.28Keywords:
acute kidney injury, apoptosis, oxidative stress, sotagliflozinAbstract
Introduction and aim. Acute kidney injury (AKI) is a life-threatening condition with limited effective pharmacological options. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown renal protective effects, the potential role of the dual SGLT1/2 inhibitor sotagliflozin in ischemia/reperfusion injury (IRI) has not been previously investigated. We aimed to evaluate its nephroprotective properties in a rat model of renal IRI.
Material and methods. Twenty-four male Sprague-Dawley rats were randomized into four groups (sham, control, dimethyl sulfoxide [DMSO], sotagliflozin). Renal IRI was induced by 40 min ischemia followed by 2 h reperfusion. Rats received either DMSO or sotagliflozin (10 mg/kg, intraperitoneally) 24 h and 1 h before surgery. Kidney function (urea, creatinine, neutrophil gelatinase-associated lipocalin [NGAL]), oxidative stress (8-iso-prostaglandin F2α [8-iso-PGF2α]), inflammation (tumor necrosis factor-alpha [TNF-α]), apoptosis (caspase-3), and histopathology were assessed.
Results. In the control group, serum urea (106.5±2.9 mg/dL), creatinine (1.52±0.09 mg/dL), and NGAL (64.5±3.6 ng/mL) were significantly higher than in the sham group (32.6±5.3, 0.89±0.06, 49.5±3.8, respectively; p<0.0001). Tissue 8-iso-PGF2α (63.8±5.9 pg/mL), TNF-α (186±7 pg/mL), and caspase 3 (120.3±6.5 pmol/L) were also elevated vs. sham (35.6±3.6, 137±7, 92.3±4.9; p<0.0001). Sotagliflozin pretreatment reduced urea (53.8±2.8 mg/dL), creatinine (1.04±0.07 mg/dL), NGAL (49.6±6.4 ng/mL), 8-iso-PGF2α (41.3±3.9 pg/mL), TNF-α (140±6.6 pg/mL), and caspase 3 (89.7±2.4 pmol/L; all p<0.0001 vs. control). Histological injury scores improved from 4.0 in control to 1.0 in the sotagliflozin group (p<0.05).
Conclusion. Sotagliflozin significantly improved renal function and histopathological damage in rats with renal IRI by attenuating oxidative stress, inflammation, and apoptosis. These findings support its potential as a candidate for further investigation in the prevention of AKI.
Downloads
References
Lewington AJ, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 2013;84(3):457-467. doi: 10.1038/ki.2013.153
Muroya Y, He X, Fan L, et al. Enhanced renal ischemia-reperfusion injury in aging and diabetes. Am J Physiol Renal Physiol. 2018;315(6):F1843-F1854. doi: 10.1152/ajprenal.00184.2018
Palevsky PM. Endpoints for Clinical Trials of Acute Kidney Injury. Nephron. 2018;140(2):111-115. doi: 10.1159/000493203
Wu HH, Huang CC, Chang CP, Lin MT, Niu KC, Tian YF. Heat shock protein 70 (HSP70) reduces hepatic inflammatory and oxidative damage in a rat model of liver ischemia/reperfusion injury with hyperbaric oxygen preconditioning. Med Sci Monit. 2018;24:8096–8104. doi: 10.12659/MSM.911641
Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: pathogenesis and treatment. World J Transplant. 2015;5(2):52. doi: 10.5500/wjt.v5.i2.52
Peiris D. A historical perspective on crush syndrome: the clinical application of its pathogenesis, established by the study of wartime crush injuries. J Clin Pathol. 2017;70(4):277-281. doi: 10.1136/jclinpath-2016-203984
Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol. 2011;7(4):189-200. doi: 10.1038/nrneph.2011.16
Zhang M, Liu Q, Meng H, et al. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2024;9(1):12. doi: 10.1038/s41392-023-01688-x
Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol. 2009;130(1):41-50. doi: 10.1016/j.clim.2008.08.016
Tweij TAR, Al-Issa MA, Hamed M, Khaleq MAA, Jasim A, Hadi NR. Pretreatment with erythropoietin alleviates the renal damage induced by ischemia reperfusion via repression of inflammatory response. Wiad Lek. 2022;75(12):2939-2947. doi: 10.36740/WLek202212108
Lytvyn Y, Kimura K, Peter N, et al. Renal and vascular effects of combined SGLT2 and angiotensin-converting enzyme inhibition. Circulation. 2022;146(6):450-462. doi: 10.1161/CIRCULATIONAHA.122.059150
Mills EL, Kelly B, O’Neill LAJ. Mitochondria are the powerhouses of immunity. Nat Immunol. 2017;18(5):488-498. doi: 10.1038/ni.3704
Cefalo CMA, Cinti F, Moffa S, et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019;18(1):20. doi: 10.1186/s12933-019-0828-y
Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139. doi: 10.1056/NEJMoa2030186
Pitt B, Steg G, Leiter LA, Bhatt DL. The role of combined SGLT1/SGLT2 inhibition in reducing the incidence of stroke and myocardial infarction in patients with type 2 diabetes mellitus. Cardiovasc Drugs Ther. 2022;36:1-7. doi: 10.1007/s10557-021-07291-y
Requena-Ibáñez JA, Kindberg KM, Santos-Gallego CG, Zafar MU, Badimon JJ. Sotagliflozin: two birds with one stone? Cardiovasc Drugs Ther. 2025. doi: 10.1007/s10557-025-07723-z
Sherratt S, Libby P, Bhatt DL, Mason P. Sotagliflozin, a dual SGLT-1/2 inhibitor, modulated expression of endothelial proteins that inhibit reactive oxygen species during inflammation compared with empagliflozin. Circulation. 2022;146(1):A13422. doi: 10.1161/circ.146.suppl_1.13422
Zeid ASS, Sayed SS. A comparative study of the use of dexamethasone, N-acetyl cysteine, and Theophylline to ameliorate renal ischemia–reperfusion injury in experimental rat models: A biochemical and immuno-histochemical approach. Saudi J Kidney Dis Transplant. 2020;31(5):982-987. doi: 10.4103/1319-2442.301203
Luo L, Liu H, Han J, Wu S, Kasim V. Intramuscular injection of sotagliflozin promotes neovascularization in diabetic mice through enhancing skeletal muscle cells paracrine function. Acta Pharmacol Sin. 2022;43(10):2636-2645. doi: 10.1038/s41401-022-00889-4
Zhong P, Zhang J, Wei Y, Liu T, Chen M. Sotagliflozin attenuates cardiac dysfunction and remodeling in myocardial infarction rats. Heliyon. 2023;9(11):e22423. doi: 10.1016/j.heliyon.2023.e22423
Alaasam ER, Janabi AM, Al-Buthabhak KM, et al. Nephroprotective role of resveratrol in renal ischemia-reperfusion injury: a preclinical study in Sprague-Dawley rats. BMC Pharmacol Toxicol. 2024 ;25(1):82. doi: 10.1186/s40360-024-00809-8
Jallawee HQ, Janabi AM. Potential nephroprotective effect of dapagliflozin against renal ischemia reperfusion injury in rats via activation of autophagy pathway and inhibition of inflammation, oxidative stress and apoptosis. South East Eur J Public Health. 2024;24:488-500. doi: 10.70135/seejph.vi.1009
Alkhafaji GA, Janabi AM. Protective effects of bexagliflozin on renal function in a rat model of ischemia-reperfusion injury: an experimental animal study. J Nephropharmacol. 2025;14(2):e12760. doi: 10.34172/npj.2025.12760
Herat L, Matthews J, Darimi A, Rakoczy P, Matthews V, Schlaich M. Sotagliflozin promotes anti-oxidant properties in the kidneys of type 1 diabetic Akimba mice. Preprints. 2024;2024020495. doi: 10.20944/preprints202402.0495.v1
Nezamoleslami S, Sheibani M, Jahanshahi F, Mumtaz F, Abbasi A, Dehpour AR. Protective effect of dapsone against renal ischemia-reperfusion injury in rat. Immunopharmacol Immunotoxicol. 2020;42(3):272-279. doi: 10.1080/08923973.2020.1755308
Alsaaty EH, Janabi AM. Moexipril improves renal ischemia/reperfusion injury in adult male rats. J Contemp Med Sci. 2024;10(1):1477. doi: 10.22317/jcms.v10i1.1477
Huang J, Shi L, Yang Y, et al. Mesenchymal cell-derived exosomes and miR-29a-3p mitigate renal fibrosis and vascular rarefaction after renal ischemia reperfusion injury. Stem Cell Res Ther. 2025;16(1):135. doi: 10.1186/s13287-025-04226-4
Lasorsa F, Rutigliano M, Milella M, et al. Ischemia–reperfusion injury in kidney transplantation: mechanisms and potential therapeutic targets. Int J Mol Sci. 2024;25(8):4332. doi: 10.3390/ijms25084332
Hadi NR, Al-Amran F, Tweij TAR, Mansur ME. CDDO-Me provides kidney protective impacts against ischemia/reperfusion injury via inhibition of oxidative stress and inflammation by targeting Nrf2 and NF-κB signaling pathways. Syst Rev Pharm. 2020;11(1):16. doi: 10.5530/srp.2020.1.16
Wang Q, Ju F, Li J, et al. Empagliflozin protects against renal ischemia/reperfusion injury in mice. Sci Rep. 2022;12(1):19323. doi: 10.1038/s41598-022-24103-x
Lu H, Zhang Y, Zhang X, et al. New insights into zinc alleviating renal toxicity of arsenic-exposed carp (Cyprinus carpio) through YAP-TFR/ROS signaling pathway. Pestic Biochem Physiol. 2024;205:106153. doi: 10.1016/j.pestbp.2024.106153
Lu H, Su H, Liu Y, et al. NLRP3 inflammasome is involved in the mechanism of the mitigative effect of lycopene on sulfamethoxazole-induced inflammatory damage in grass carp kidneys. Fish Shellfish Immunol. 2022;123:348-357. doi: 10.1016/j.fsi.2022.03.018
Basu S, Meisert I, Eggensperger E, Krieger E, Krenn CG. Time course and attenuation of ischemia-reperfusion induced oxidative injury by propofol in human renal transplantation. Redox Rep. 2007;12(4):195-203. doi: 10.1179/135100007X200281
Li FF, Gao G, Li Q, et al. Influence of dapagliflozin on glycemic variations in patients with newly diagnosed type 2 diabetes mellitus. J Diabetes Res. 2016;2016:5347262. doi: 10.1155/2016/5347262
Woods TC, Satou R, Miyata K, et al. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol. 2019;49(4):331-342. doi: 10.1159/000499597
Lu H, Guo T, Zhang Y, et al. Endoplasmic reticulum stress-induced NLRP3 inflammasome activation as a novel mechanism of polystyrene microplastics (PS-MPs)-induced pulmonary inflammation in chickens. J Zhejiang Univ B. 2024;25(3):233-243. doi: 10.1631/jzus.B2300409
Shan Y, Chen D, Hu B, et al. Allicin ameliorates renal ischemia/reperfusion injury via inhibition of oxidative stress and inflammation in rats. Biomed Pharmacother. 2021;142:112077. doi: 10.1016/j.biopha.2021.112077
Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol Res. 2021;9944880. doi: 10.1155/2021/9944880
Zhang Z, Li L, Dai Y, et al. Dapagliflozin inhibits ferroptosis and ameliorates renal fibrosis in diabetic C57BL/6J mice. Sci Rep. 2025;15(1):7117. doi: 10.1038/s41598-025-91278-4
Yang W, Li X, He L, et al. Empagliflozin improves renal ischemia-reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK-OPA1 pathway promotion. Cell Mol Biol Lett. 2023;28(1):42. doi: 10.1186/s11658-023-00457-6
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 European Journal of Clinical and Experimental Medicine
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.
