Abstract
BackgroundNinety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is enhanced under diabetic conditions, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. However, it remains unclear which diabetes-associated factors are involved in overexpression of SGLT2.MethodsTherefore, in this study, we examined whether insulin, high glucose, advanced glycation end products (AGEs), or H2O2 stimulated SGLT2 expression in human cultured proximal tubular cells, and then investigated the underlying molecular mechanisms.ResultsHigh glucose or AGEs did not affect SGLT2 expression in tubular cells. Insulin significantly increased tubular SGLT2 level in a dose-dependent manner, whereas bell-shaped dose-response curves were observed for H2O2-treated cells. An anti-oxidant, N-acetylcysteine completely blocked insulin-induced up-regulation of SGLT2 as well as increase in glucose absorption by tubular cells. Furthermore, insulin dose-dependently increased reactive oxygen species generation in tubular cells.ConclusionsOur present study demonstrated that insulin could stimulate SGLT-2-mediated glucose entry into cultured proximal tubular cells via oxidative stress generation. Suppression of the insulin-induced overexpression of SGLT2 in tubular cells might be a novel therapeutic strategy for the treatment of diabetic nephropathy.
Highlights
Diabetic nephropathy is a leading cause of end-stage renal disease, which could account for disabilities and high mortality rates in patients with diabetes [1, 2]
We have previously shown that increased glucose uptake into cultured renal proximal tubular cells via sodium-glucose cotransporter 2 (SGLT2) stimulates oxidative stress generation and resultantly potentiates the pro-apoptotic effects of advanced glycation end products (AGEs), senescent macroprotein derivatives formed acceleratedly under diabetes, on tubu
High glucose, AGEs, or H2O2 on SGLT2 expression We first examined whether insulin, high glucose, AGEs, or H2O2 stimulated SGLT2 expression in cultured proximal tubular cells
Summary
Diabetic nephropathy is a leading cause of end-stage renal disease, which could account for disabilities and high mortality rates in patients with diabetes [1, 2]. Ninety percent of glucose filtered by the glomerulus is reabsorbed by a low-affinity/high capacity sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on S1 and S2 segment of renal proximal tubules [6,7,8]. Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is enhanced under diabetic conditions, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. It remains unclear which diabetes-associated factors are involved in overexpression of SGLT2
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