Canagliflozin selectively inhibits SGK1 expression and NHE activity in kidney and heart cells

Sodium glucose cotransporter 2 inhibitors (SGLT2i) treat hyperglycemia in diabetics by blocking glucose reabsorption in the kidney proximal tubule (PT) through a shared class effect. Clinical studies revealed these drugs have benefits beyond glycemic control including improving heart failure outcomes in diabetic and non-diabetic patients. SGLT2i are now being investigated in a plethora of other diseases for potential beneficial effects including cancer, neurodegeneration, and metabolic liver disease. However, few studies compare SGLT2i against one another even though emerging evidence suggests variability in drug action may be from noncanonical effects specific to each drug. Direct comparative studies between SGLT2i are needed to better understand these drug-specific effects and their functional impacts. We recently reported on differential effects of canagliflozin vs empagliflozin on fluid transport and albumin uptake in vitro in opossum kidney PT cells (OK cells) and demonstrated differential effects in mouse models. To assess whether SGLT2i show differential effects on signaling we examined the effects of SGLT2i on serum- and glucocorticoid-related kinase 1 (SGK1) expression in OK cells and rat cardiomyocytes (H9C2 cells). We found canagliflozin decreased SGK1 expression temporally in both kidney and heart cells while dapagliflozin and empagliflozin did not. Since SGK1 also regulates sodium hydrogen exchanger (NHE) activity, we acid-loaded both cell types and assayed intracellular pH recovery to determine if NHE activity was also affected. Canagliflozin, but neither dapagliflozin nor empagliflozin, inhibited pH recovery in both kidney and heart cells. Current studies are continuing to assess the signaling pathways that canagliflozin differentially affects to confer these noncanonical effects. This abstract was presented at the American Physiology Summit 2026 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.