Abstract: FR-OR045
Dual SGLT1/2 Inhibition Attenuates Salt-Sensitive Hypertension and Kidney Injury More Effectively than SGLT2 Inhibition
Session Information
- Hypertension and Cardiorenal Disease: Novel Mechanisms and Therapeutic Targets
November 07, 2025 | Location: Room 332A, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Kravtsova, Olha, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
- Levchenko, Vladislav, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
- Upadhyay, Gunjan D, University of South Florida, Tampa, Florida, United States
- Bohovyk, Ruslan, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
- Liu, Ruisheng, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
- Rieg, Timo, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
- Halade, Ganesh V, University of South Florida, Tampa, Florida, United States
- Staruschenko, Alexander, University of South Florida Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for glycemic control in type 2 diabetes, have since demonstrated significant cardiovascular and renal protective effects. The recent FDA approval of the dual SGLT1/2i sotagliflozin (Sota) for HFpEF and HFrEF underscores the therapeutic potential of SGLT inhibition. However, the mechanistic roles of SGLT2i and SGLT1/2i in salt-sensitive hypertension (SS HTN) are not well understood. This study aims to define the effects of SGLT inhibition on SS HTN and associated mechanisms.
Methods
Eight-week-old Dahl SS rats of both sexes were treated with dapagliflozin (Dapa; 2 mg/kg/day) or Sota (30 mg/kg/day) for 3 weeks while maintained on a high salt diet (4% NaCl). Blood pressure was monitored continuously by radiotelemetry. Transcriptomic and lipidomic analyses were performed on tissues and biological fluids.
Results
Our previous studies demonstrated that Dapa prevented the development of SS HTN in both male and female Dahl SS rats without altering sodium channel expression or the renin-angiotensin-aldosterone system. Moreover, when given therapeutically (after hypertension develops), Dapa still reduced blood pressure, although the effect was less profound. Compared to Dapa, Sota had a greater impact on reducing MAP (Sota vs. vehicle: males, 126 ± 2 vs. 157 ± 5 mmHg; females,126 ± 3 vs. 167 ± 10 mmHg) after 3 weeks without affecting heart rate (HR). When fed a normal salt diet (0.4% NaCl), Sota did not affect MAP or HR. Relative to Dapa, Sota reduced body weight, increased urinary Na+ and Cl- excretion (1.45 and 1.49-fold, respectively), and led to greater fractional glucose excretion (Dapa vs. Sota: 23 vs.48%). Neither treatment affected glomerular filtration rate. In Dapa-treated animals, kidney tissue showed enrichment in lipid metabolism and inflammatory pathways. Interestingly, fatty acid metabolism was predicted to be downregulated in the cortex and upregulated in the medulla. This difference was aligned with shifts in the lipid mediators' profile.
Conclusion
Dual SGLT1/2 inhibition more effectively reduces SS HTN and renal injury compared to SGLT2 inhibition. These findings suggest distinct and possibly additive mechanisms, warranting further investigation of underlying molecular pathways.