Canagliflozin-selective inhibition of Sgk1 reduces endocytosis in proximal tubule cells

Beyond glycemic control, Sglt2 inhibitors (Sglt2i) have protective effects on renal function. Off target effects have been proposed to account for some of the renoprotective effects of SGLT2i. We recently reported that canagliflozin rapidly (within 15 min) inhibits albumin endocytosis.in opossum kidney (OK) proximal tubule (PT) cells while empagliflozin has no effect. The mechanisms responsible for the rapid reduction of endocytosis in canagliflozin treated cells are unknown. Because Sgk1 contributes to albumin uptake in PT cells, we asked whether canagliflozin affects Sgk1 activity. Strikingly, canagliflozin reduced Sgk1 expression levels within 15 min of exposure. Effects were observed at concentrations as low as 10 µM, comparable to plasma levels of canagliflozin measured in humans. Inhibition of Sgk1 using GSK phenocopied the effect of canagliflozin on albumin uptake. Canagliflozin also reduced AKT phosphorylation at Ser473, suggesting involvement of the PI3K/mTORC2 pathway. Current studies are aimed at identifying the molecular target of canagliflozin. Cultural Mission of the Royal Embassy of Saudi Arabia (SACM) ASN Pre-doctoral fellowship Dialysis Clinic Inc. NIH This abstract was presented at the American Physiology Summit 2025 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.