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Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors are new, highly effective drugs for treating type 2 diabetes mellitus. SGLT2 inhibitors also substantially reduced the risk of hospitalization for heart failure. Previous studies in rodents and humans have shown that SGLT2 inhibitors lower blood pressure levels, cardiovascular risk events, and kidney diseases in subjects with and without diabetes mellitus. However, the mechanisms behind those effects are still unknown. Our previous study showed that SGLT2 inhibition blunted the development of salt-sensitive (SS) hypertension and caused glucosuria and natriuresis in Dahl SS rats without affecting the expression and activity of Na+ channels and changes in the renin-angiotensin-aldosterone system. Here, we aim to investigate the effect of SGLT2 treatment on non-diabetic SS rats using multi-omics analysis, which may provide insights into the underlying mechanisms. 8-week-old male SS rats were treated with or without SGLT2 inhibitor (dapagliflozin, 2 mg/kg/day in drinking water) for 3 weeks. Kidney cortex and medulla tissue were collected for RNA-Seq analysis. Proteomics analysis was performed on kidney cortex tissue and plasma. The data were further processed by Ingenuity Pathway Analysis (IPA).RNA-Seq analysis indicated that despite SLGT2 mainly being expressed in the kidney cortex, dapagliflozin treatment altered the expression of more genes in the medulla (855 in the cortex vs 2244 differentially expressed genes (DEGs) in the medulla). Dapagliflozin treatment also caused significant changes in multiple genes related to inflammation and hypertension, with IPA analysis predicting the downregulation of both functions. In hypertension network Adrb3, Retn, Foxn4 were the most upregulated genes, and Ptgs1, Nos1, Oxtr – downregulated. In addition, disease and biological function enrichment analysis revealed that the altered genes were mainly related to the following functions: lipid metabolism, small molecule biochemistry, amino acid metabolism, cell cycle and morphology, and molecular transport. Interestingly, lipid metabolism was predicted to be downregulated in the cortex but upregulated in the medulla.Proteomic analysis identified 450 differentially expressed proteins (DEPs) in the kidney cortex and 22 in plasma. Disease and biological function enrichment analysis on proteomics data revealed mostly the same biological functions as RNA-Seq data. In addition, canonical pathways analysis based on RNA-Seq and proteomics data revealed that endothelin-1 and oxytocin signaling pathways were the most downregulated pathways in the kidney cortex and medulla under the dapagliflozin treatment. Urea cycle and glucocorticoid receptor signaling were the most changed canonical pathway in proteomic data. In conclusion, our results indicated that inhibition of SGLT2 by dapagliflozin altered various genes and proteins in the kidney of Dahl SS rats, which may provide insights for future mechanistic studies. This research was supported by National Institutes of Health grants R35 HL135749 (to AS). This is the full abstract presented at the American Physiology Summit 2023 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.