Abstract P213: Multi-omic Analysis Of The Effect Of SGLT2 Inhibition On Blood Pressure In Dahl SS Rats

SGLT2 inhibitors (SGLT2i) have demonstrated efficacy in reducing heart failure, lowering blood pressure, and mitigating kidney diseases in both diabetic and non-diabetic conditions. Previously, we demonstrated the preventive effects of the SGLT2i dapagliflozin (Dapa) on salt-sensitive hypertension (SS HTN) in male Dahl SS rats (Dapa vs. vehicle: 136±3 vs. 156±6 mmHg) (Kravtsova et al ., AJP Renal 2022). In the current study, we aimed to assess whether Dapa has similar outcomes in female rats. Our findings reveal that Dapa administration (2 mg/kg/day in drinking water for 3 weeks) resulted in a comparable effect on blood pressure in female rats (Dapa vs. vehicle: 140±5 vs. 160±9 mmHg). We further performed transcriptomic and proteomic analyses of the kidney cortex and medulla in both male and female rats fed a high salt (HS) diet, with or without Dapa. Both analyses revealed that the top biological functions affected by Dapa were related to lipid and amino acid metabolism, molecular transport, and cell function. The enrichment analysis of biological functions highlighted altered genes primarily associated with fatty acid oxidation, lipid transport and oxidation, and ion homeostasis primarily in the medulla. Notably, Plin1 , Plin4 , Ucp1 , Ucp3 and Adrb3 , which are involved in lipid metabolism, were the highest expressed genes in the kidney medulla of both sexes. Based on previous studies suggesting the involvement of oxidized phospholipids and metabolites of linoleic and arachidonic acids in the pathogenesis of SS HTN, we conducted preliminary experiments with males to assess the levels of lipid mediators in the kidneys of Dapa-treated rats. HS diet in Dahl SS rats led to elevated levels of several pro-inflammatory mediators, which were significantly reduced in Dapa-treated rats. These reductions were observed for prostaglandins (PGD2 [fold change (FC)=0.28], PGF2a [FC=0.14], 8-iso-PGF2a [FC=0.14]), 12-HHT [FC=0.31], TXB2 [FC=0.18], and 20-OH-LTB4 (FC=0.10). Our results indicated that SGLT2i altered various genes in the kidneys of Dahl SS rats independent of sex. This information provides novel insight on the pleiotropic effects of SGLT2i. Further studies are necessary to validate the predicted targeted pathways and subsequent biological functions.