Effect of SGLT2 and dual SGLT1/2 Inhibition on the Development of Salt-induced Hypertension

Abstract

In recent years, sodium-glucose co-transporter inhibitors (SGLT2i) have become the new mainstay in treating diabetes mellitus and, lately, cardiovascular diseases. Large clinical trials have shown remarkable benefits of SGLT2i on renal and cardiovascular outcomes. SGLT2i have been reported to slow the progression of chronic kidney disease by reducing hyperfiltration and glomerular capillary pressure, kidney hypertrophy, and albuminuria. Recently, the dual SGLT1/2 inhibitor sotagliflozin (Sota) was approved by the FDA for the treatment of heart failure independent of ejection fraction. However, despite these promising outcomes, the effects of SGLTi, particularly in salt-sensitive hypertension, requires further investigation. The main goal of this study was to define the effects of SGLT inhibition on the development of salt-induced hypertension and characterize potential contributing mechanisms. In our recent studies, we showed that SGLTi dapagliflozin (Dapa) caused an increase of diuresis in 8-weeks old male and female Dahl SS rats when fed a high salt (HS, 4% NaCl for 3 weeks) diet. Additionally, Dapa increased glucose and Na+ excretion. Chronic Dapa treatment also resulted in inhibition of the development of hypertension. Interestingly, male rats had no changes in kidney damage, whereas in females Dapa attenuated kidney fibrosis. To define potential molecular mechanisms involved in the beneficial effects of SGLT2i, we performed additional analyses of tissues collected from SS rats on a HS diet treated with either vehicle or Dapa. Transcriptomics analyses revealed that in the kidney cortex, top biological functions affected by SGLT2 inhibition were related to lipid and amino acid metabolism, molecular transport, as well as cell function. Preliminary studies were performed to test lipid mediators in the kidney cortex of male Dahl SS rats fed 3 weeks with HS diet and treated with Dapa. We found that several tested bioactive lipids, specifically pro-inflammatory mediators, were elevated in Dahl SS rats following HS diet, and these increased levels were completely blocked in Dapa-treated rats. Dual SGLT1/2 inhibition by Sota (30 mg/kg/day in food, n=6 rats/group) resulted in rapid attenuation of salt-induced hypertension. Starting from day 5 of HS challenge, MAP of vehicle-treated Dahl SS male rats was significantly higher compared to Sota-treated rats (~33 mmHg MAP difference on day 21), whichout differences in heart rate. In response to Sota treatment, SS rats had ~1.6-fold greater diuresis (at day 21: vehicle 37±2 vs. treated 61±6 ml/day) and glucosuria (values?). Further studies are ongoing to define the effects on GFR, kidney, and heart damage, and the potential resulting mechanisms. Our preliminary data indicate that dual SGLT1/2 inhibition with Sota had a significant impact on salt-induced hypertension in the Dahl SS rats. Further research will provide a more comprehensive understanding of the mechanisms. This research was supported by National Institutes of Health grant R35 HL135749 (to AS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.