Dapagliflozin Decrease Fructose-Induced Oxidative Stress Mediated by AGE- MMP9 via a SGLT-2-Dependent Mechanism in the Lens of Type 2 DM Model

[Speaker] Ying-Ying Chen:1
[Co-author] Tsung-Tien Wu:2, Pei-Wen Cheng:3
1:Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, 2:National Yang-Ming University, Taipei, Taiwan, 3:Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

Background and purpose: Cataracts in patients with diabetes are a major cause of blindness in developed and developing countries. The present findings describe the effects of altered glucose homeostasis on glucose transport and energy metabolism in the eye. Great deals of studies have demonstrated that chronic hyperglycemia-induced overproduction of reactive oxygen species (ROS) played a central role in the pathogenesis of diabetic cataract. Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been developed to enable glycemic control in T2DM patients. The aim of this study was to examine whether generation of ROS through a SGLT2 enhanced AGE and MMP9 production in lens epithelial cells (LECs) from DM patients and in a rat DM model.
Methods: Fluorescence was used to estimate the 3-Nitrotyrosine and SGLT2 levels in the human lens epithelial sections from DM or non-DM cataracts. Both the fructose-fed group and the treatment group were fed with 10 percent fructose for 8 weeks and the treatment group was treated with Dapagliflozin (1.2 mg/day) beginning at week 6 to 8. Besides, plasma HbA1c level of the patients and rats was measured by Clinical Chemistry Analyzer. Immunoblotting analyses were used to quantify protein levels in the rat lens epithelial cell.
Results: Immunofluorescent staining also demonstrated that 3-Nitrotyrosine was significantly enhanced both in the human lens epithelial sections from DM or non-DM cataracts. Interestingly, SGLT2 levels were significantly higher in the LECs of the patients with DM, not in non-DM cataracts. These results indicated that SGLT2 may be required for induced superoxide generation and the pathogenesis of diabetic cataract formation.
Besides, AGE, SGLT2 and MMP9 were significantly enhanced in the lens epithelial of after feeding the fructose for 8 weeks, whereas dapagliflozin treatment reversed this effect in the fructose-fed rats. Conclusions: Collectively, fructose increased SGLT2, AGE and MMP9 in the lens of fructose-fed rats, while treatment with Dapagliflozin reversed the effect in the rat lens epithelial cell of fructose-induced diabetes, similar to patients with DM. These novel findings suggest that the Dapagliflozin may be a potential pharmacological candidate for preventing diabetic cataract.

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