Ninety percent of
glucose filtered by the glomerulus is reabsorbed by a
sodium-glucose cotransporter 2 (SGLT2), which is mainly expressed on S1 and S2 segment of renal proximal tubules. Since SGLT-2-mediated
glucose reabsorption is increased under diabetic conditions, selective inhibition of SGLT2 is a potential therapeutic target for the treatment of diabetes. We have recently shown that an inhibitor of SGLT2 has anti-inflammatory and antifibrotic effects on experimental
diabetic nephropathy partly by suppressing
advanced glycation end products formation and oxidative stress generation in the kidney. However, the direct effects of
SGLT2 inhibitor on tubular cell damage remain unclear. In this study, we investigated the effects of
tofogliflozin, a highly selective inhibitor of SGLT2 on oxidative stress generation, inflammatory and proapoptotic reactions in cultured human proximal tubular cells exposed to high
glucose.
Tofogliflozin dose-dependently suppressed
glucose entry into tubular cells. High
glucose exposure (30 mM) for 4 and 24 h significantly increased oxidative stress generation in tubular cells, which were suppressed by the treatment of
tofogliflozin or an
antioxidant N-acetylcysteine (NAC).
Monocyte chemoattractant protein-1 (MCP-1) gene expression and apoptotic cell death were induced by 4 h- and 8 day-exposure to high
glucose, respectively, both of which were also blocked by
tofogliflozin or NAC. The present study suggests that SGLT2-mediated
glucose entry into tubular cells could stimulate oxidative stress and evoke inflammatory and proapoptotic reactions in this cell type. Blockade of
glucose reabsorption in tubular cells by
SGLT2 inhibitor might exert beneficial effects on tubulointerstitial damage in
diabetic nephropathy.