Hypertension affects nearly half of U.S. adults and more than 1.3 billion individuals worldwide; it also remains a major cause of end-stage renal disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), first introduced for the management of type 2 diabetes mellitus, have consistently demonstrated protective effects on kidney function and the cardiovascular system in individuals with or without diabetes. In Dahl salt-sensitive (SS) rats, prior studies have shown that SGLT2i attenuates the progression of hypertension (Kravtsova et al., 2022; Kravtsova et al., 2023). Additionally, SGLT2i are now incorporated into first-line therapeutic regimens for individuals with heart failure with reduced ejection fraction due to their protective effects on cardiovascular remodeling. Despite these established clinical benefits, the molecular and physiological mechanisms by which SGLT2i confers renal and cardiovascular protection remain incompletely understood. To address this knowledge gap, the present study investigated potential pleiotropic effects of SGLT2i on blood pressure regulation in a SS hypertension using a novel genetic SGLT2 knockout (KO) model. SGLT2 KO Dahl SS rats showed attenuated hypertension on a high-salt (4% NaCl) diet, with lower mean arterial pressure (MAP) by day 28 (156 ± 5 vs 174 ± 8 mmHg, P=0.01). To further evaluate the impact of SGLT2i, eight-week-old male SGLT2 KO rats were randomized to either vehicle or SGLT2i (2 mg/kg/day, via drinking water), while being maintained on a high-salt diet for 28 days. Physiological parameters, including continuously measured mean arterial pressure (MAP) and heart rate using radiotelemetry, food and water intake, urinary flow rate, urine electrolytes, urinary albumin and creatinine, and glomerular filtration rate (GFR), were measured throughout the study. At study termination, organ weights and plasma electrolytes were determined. Administration of dapagliflozin to SGLT2 KO rats did not produce additive effects on MAP, heart rate, kidney weight, GFR, or diuresis compared with vehicle-treated SSSGLT2-/- controls. At the end of the study, both dapagliflozin-treated and untreated SGLT2 KO rats maintained similarly reduced MAP compared with SS wild-type rats. No significant differences were observed in food or water intake or organ weights between the two SGLT2 KO groups. This study was designed to define potential off-target effects or pathways through which SGLT2 inhibitors exert their cardiovascular and renal benefits. Our findings indicate that pharmacologic SGLT2 inhibition does not further reduce blood pressure or enhance renal function in SGLT2-deficient SS rats, suggesting that the antihypertensive and renoprotective effects observed in wild-type SS rats are primarily mediated by SGLT2-dependent mechanisms. Future studies will assess whether SGLT2 inhibition alters urinary electrolyte excretion and SGLT1 abundance in the kidneys. This research was supported by National Institutes of Health grants 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.
Barranco et al. (Fri,) studied this question.