Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis.

BACKGROUND

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. Because blockade of SGLT2 promotes urinary glucose excretion and thereby improves hyperglycaemia, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. Moreover, advanced glycation end products (AGEs)-receptor (RAGE) system induces apoptosis of tubular cells, thereby playing a role in diabetic nephropathy as well. However, the pathophysiological crosstalk of SGLT2 with AGEs-RAGE axis and its role in diabetic nephropathy remains unknown.

METHODS

This study investigated whether and how blockade of SGLT2 could prevent AGEs-elicited apoptosis of high glucose-exposed proximal tubular cells in vitro.

RESULTS

SGLT2 was expressed in tubular cells. Tubular SGLT2 expression and glucose entry into the cells were completely blocked by the treatment with small interfering RNAs (siRNAs) raised against SGLT2. High glucose increased reactive oxygen species generation and RAGE expression levels in tubular cells, both of which were partly suppressed by SGLT2 siRNAs or an antioxidant, N-acetylcysteine. Further, high glucose was found to augment the AGEs-induced tubular cell apoptosis, which was also inhibited by SGLT2 siRNAs.

CONCLUSIONS

Our present data suggest that SGLT2-mediated, high glucose-induced reactive oxygen species generation could augment the AGEs-induced apoptotic cell death of tubular cells via RAGE induction. SGLT2 may play some role in tubular apoptosis in diabetic nephropathy.