Abstract Body: The dual inhibition of sodium-glucose co-transporter 1 and 2 (SGLT1/SGLT2) presents a novel therapeutic approach to cardiovascular diseases. The FDA recently approved the dual SGLT1/2 inhibitor sotagliflozin (Sota) for treating heart failure regardless of ejection fraction. However, our understanding of the effects and mechanisms of SGLT2 and dual SGLT1/2 inhibitors in salt-sensitive hypertension (SS HTN) remains limited. Thus, additional studies are needed to reveal the role and mechanism(s) of SGLTi in SS hypertension. In our previous studies, we demonstrated the beneficial effect of SGLT2i dapagliflozin (Dapa) on SS HTN in male and female Dahl SS rats on blood pressure (MAP after 3 weeks on high salt diet were: Dapa vs. vehicle: 136 ± 3 vs. 156 ± 6 mmHg in males and 140 ± 5 vs. 160±9 mmHg in females). This study aims to define the effects and potential mechanisms of dual SGLT1/2 inhibition in managing SS HTN. Dual SGLT1/2 inhibition with Sota (30 mg/kg/day) prevented the development of SS HTN in Dahl SS in both sexes without changes in heart rate. By the 21^st day of the high-salt challenge, MAP was lower more than 30 mmHg in treated groups (Sota vs. vehicle: male rats 126 ± 2 vs 157 ± 5 mmHg (N=7, p=0.0002); female rats 126 ± 3 vs 167 ± 10 mmHg (N=6, p=0.0095). Under Sota treatment, rats had significantly increased diuresis (Sota vs. vehicle: males 69 ± 3 vs 35 ± 2 ml and females 48 ± 5 vs 31 ± 2 ml on day 21), glucose and sodium excretion. In both sexes, Sota treatment resulted in a lower heart-to-body weight ratio, and kidney weight was not changed. Also, Sota attenuated kidney fibrosis and protein cast formation (Sota vs. vehicle: cortex fibrosis in males 2.3 ± 0.4 vs 4.6 ± 0.5 % and females 2.0 ± 0.2 vs 4.0 ± 0.7 %, outer medullary protein casts in males 2.5 ± 0.2 vs 16.0 ± 2.6 % and 1.9 ± 0.3 vs 7.5 ± 0.9 % in females) without changes in albuminuria in both sexes. However, no changes in glomerular filtration rate or creatine clearance were detected. Based on our data, it can be inferred that dual SGLT1/2 inhibition prevents the development of SS HTN and kidney damage. Potential mechanisms underlying those beneficial effects of SGLT1/2 inhibition will be further explored.