The effect of SGLT2 inhibitor on the gene expression and metabolomic profile of podocytes

Background Podocyte injury due to hyperglycemia is a key driver of diabetic kidney disease (DKD). Although sodium-glucose co-transporter 2 inhibitor (SGLT2i) act primarily on the proximal tubule, they may have direct effects on podocyte. We investigated the effect of dapagliflozin on the transcriptomic and metabolomic profiles of cultured human podocytes under high glucose. Methods Primay culture of human podocytes were exposed to normal (5 mM) or high glucose (25 mM) with or without dapagliflozin (11 nM) for 48 hours. Targeted cellular metabolome analysis by capillary electrophoresis time of flight mass spectrometer (CE-TOF/MS) and capillary electrophoresis-triple quadrupole mass spectrometry (CE-QqQMS) quantified 116 metabolites. RNA sequencing assessed transcriptomic changes. Results Both transcriptomic and metabolomic analyses showed that high glucose and dapagliflozin treatment showed distinct clustes. High glucose upregulated genes and metabolites involved in glycolysis, gluconeogenesis, fatty acid, and amino acid metabolism, while reducing arginine biosynthesis. Gene set enrichment analysis (GSEA) indicated that treatment with dapagliflozin partially normalize these metabolic disturbances. Metabolomic shifts in glycolysis, the citric acid cycle, pentose phosphate pathway, and arginine biosynthesis under high glucose were also substantially reversed by dapagliflozin. Conclusion Dapagliflozin restores dysregulated carbohydrate, amino acid, and arginine metabolism in podocytes exposed to high glucose. These results suggest that SGLT2i has direct protective effect on podocytes in a diabetic milieu.