Comparative effects of dual SGLT1/2 and SGLT2 Inhibitorson salt-sensitive hypertension and kidney injury

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have emerged as effective treatments for type 2 diabetes and cardiovascular diseases, showing substantial improvements in renal and cardiovascular outcomes in large clinical trials. The FDA's recent approval of the dual SGLT1/2 inhibitor sotagliflozin (Sota) for heart failure treatment highlights a new therapeutic direction. However, the specific effects and mechanisms of both SGLT2 and dual SGLT1/2 inhibitors on salt-sensitive hypertension (SS HTN) remain not fully understood. This study aims to define the effects of SGLT inhibition on the development of SS HTN and determine potential mechanisms contributing to these effects. Our previous studies showed the blood pressure lowering effect of SGLT2i dapagliflozin (Dapa) (2 mg/kg/day) on SS HTN in male and female Dahl SS rats (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). Experiments with dual SGLT1/2 inhibition by Sota (30 mg/kg/day) resulted in a more profound effect on SS HTN (Sota vs. vehicle: 126 ± 2 vs. 157 ± 5 mmHg in males and 126 ± 3 vs. 167 ± 10 mmHg in female). Both treatments had no effect on heart rate. On a low salt (0.4% NaCl) diet, Sota had no effect on blood pressure or heart rate. Both Dapa and Sota resulted in greater diuresis and increased glucose and electrolyte (Na + , Cl - ) excretion. No changes in fasting blood glucose were observed. Kidney weight was not changed in the Sota-treated group but increased in males Dapa-treated. 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). Dapa attenuated kidney fibrosis only in females. No changes in glomerular filtration rate or creatinine clearance were detected. The heart-to-body weight ratio was significantly lower in Sota-treated animals (Sota vs. vehicle: 3.6 ± 0.1 vs 4.1 ± 0.1 mg/g) and trending towards it in Dapa-treated. No changes in the collagen amount in the hearts were found. To investigate the mechanisms underlying the effects of SGLTi, we conducted further analyses on tissue and fluid samples of vehicle-, Sota- or Dapa-treated rats. Ingenuity pathway analysis of transcriptomics and proteomics kidney cortex datasets revealed that lipid and amino acid metabolism, molecular transport, and cell function were affected by Dapa. “Oxidative phosphorylation” and “Fatty acid metabolism” were altered in Dapa kidneys on pathway enrichment analysis. Sota treatment affected the “Complement and coagulation cascades” in the kidney cortex and structural and contractile components in the heart. Initial experiments examining lipid mediators showed that dapagliflozin inhibited pro-inflammatory mediators in the kidney cortex. Our data indicate that dual SGLT1/2 inhibitors are more effective at preventing SS HTN and kidney damage compared to SGLT2 inhibitors alone. Future studies will further investigate the mechanisms and targeted pathways involved in the effects of SGLT1/2 inhibition. This abstract was presented at the American Physiology Summit 2025 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.