Glucose filtered in the glomerulus is actively reabsorbed by
sodium-
glucose co-transporter 2 (SGLT2) in proximal tubular epithelial cells (PTEC) and passively returned to the blood via
glucose transporter 2 (GLUT2). Healthy PTEC rely primarily on
fatty acid beta-oxidation (FAO) for energy. In phase III trials,
SGLT2 inhibitors improved outcomes in
diabetic kidney disease (DKD). Tubulointerstitial renal
fibrosis due to altered metabolic reprogramming of PTEC might be at the root of the pathogenesis of DKD. Here, we investigated the molecular mechanism of
SGLT2 inhibitors' renoprotective effect by examining transcriptional activity of Spp1, which encodes
osteopontin, a key mediator of tubulointerstitial renal
fibrosis. With primary cultured PTEC from Spp1-enhanced
green fluorescent protein knock-in mice, we proved that in high-
glucose conditions, increased SGLT2- and GLUT-mediated
glucose uptake is causatively involved in aberrant activation of the glycolytic pathway in PTEC, thereby increasing mitochondrial
reactive oxygen species (ROS) formation and transcriptional activation of Spp1. FAO activation did not play a direct role in these processes, but elevated expression of a tubular-specific
enzyme,
myo-inositol oxygenase, was at least partly involved. Notably,
canagliflozin blocked overexpression of
myo-inositol oxygenase. In conclusion,
SGLT2 inhibitors exerted renoprotective effects by inhibiting aberrant glycolytic metabolism and mitochondrial ROS formation in PTEC in high-
glucose conditions.