SGLT2 knockout attenuates salt-induced hypertension in Dahl SS rats

Nearly 120 million American adults have hypertension (HTN), which is one of the major risk factors for heart attack, stroke, renal and heart failure. Salt-sensitive hypertension (SS HTN) is present in ~50% of hypertensive patients, along with its associated kidney and cardiovascular complications. Sodium-glucose transporter 2 inhibitors (SGLT2i), initially developed for type 2 diabetes mellitus, have demonstrated renoprotective and cardioprotective effects in both diabetic and non-diabetic populations. However, the specific effects and mechanisms of SGLT2i on SS HTN remain poorly understood. The present study aims to define the contribution of SGLT2 to the development of SS HTN and kidney injury using a novel genetically modified model on the Dahl SS rat background. We previously demonstrated (Kravtsova et al., 2022; Kravtsova et al., 2023) that administration of the SGLT2i dapagliflozin (Dapa) (2 mg/kg/day, drinking water) attenuated SS HTN in male and female Dahl SS rats. After three weeks on a high-salt (4% NaCl; HS) diet, mean arterial pressure (MAP) was significantly lower in Dapa-treated animals compared with vehicle controls (males: 136±3 vs. 156±6 mmHg; females: 140±5 vs. 160±9 mmHg). Building on these findings, we established an SGLT2 knockout (KO) model to directly evaluate its role in blood pressure regulation in SS HTN. On a low-salt (0.4% NaCl) diet, we have not observed differences in blood pressure between KO and wild-type (WT) 12-week-old male animals. However, KO rats had greater diuresis than WT (17±1 vs 10±1 ml/24h) and ~25% higher kidney weight. On the HS diet, KO rats exhibited a significant attenuation of hypertension, with reduced MAP on day 28 (156±5 vs 174±8 mmHg, P=0.01). KO animals showed greater urinary glucose and calcium excretions, whereas sodium, potassium, and chloride excretions were not different. Glomerular filtration rate was not significantly different between WT and KO. On the HS diet, KO rats showed greater kidney weight (~1.5-fold) compared with WT rats, accompanied by lower heart weight. Notably, albuminuria was elevated in KO animals compared to WT (Alb/Cre: 35±7 vs 12±1, P=0.02). Our results demonstrate that loss of SGLT2 attenuates salt-induced hypertension with minimal changes in kidney function. These findings highlight an important role of SGLT2 in the development of salt-induced hypertension, underscoring the need to investigate downstream pathways that mediate blood pressure regulation. Support or Funding Information This research was supported by National Institutes of Health grants R01 DK135644 (to AS), R25 DK13432 (to JB and TR) and T32 HL160529 (to RB), and USF Hypertension and Kidney Research Center Early Investigator Awards (to OK) and Multi-PI Award (to TR, RL, and AS). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.