Herat Lakshini Y, Matthews Jennifer R, Ong Wei E, Rakoczy Elizabeth P, Schlaich Markus P, Matthews Vance B
Dobney Hypertension Centre, School of Biomedical Science - Royal Perth Hospital Unit, University of Western Australia, 6009 Crawley, WA, Australia.
Department of Molecular Ophthalmology, University of Western Australia, 6009 Crawley, WA, Australia.
Front Biosci (Landmark Ed). 2022 Dec 12;27(12):321. doi: 10.31083/j.fbl2712321.
Diabetic retinopathy (DR) is a major cause of blindness globally. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have been demonstrated to exert cardiorenal protection in patients with diabetes. However, their potential beneficial effect on DR is less well studied. The aim of the present study was to determine the effects of the SGLT2 inhibition with Dapagliflozin (DAPA) on DR in well-characterised DR mouse models and controls.
Dapagliflozin was administered to mice with and without diabetes for 8 weeks via their drinking water at 25 mg/kg/day. Urine glucose levels were measured weekly and their response to glucose was tested at week 7. After 8 weeks of treatment, eye tissue was harvested under terminal anaesthesia. The retinal vasculature and neural structure were assessed using immunofluorescence, immunohistochemistry and electron microscopy techniques.
Dapagliflozin treated DR mice exhibited metabolic benefits reflected by healthy body weight gain and pronounced glucose tolerance. Dapagliflozin reduced the development of retinal microvascular and neural abnormalities, increased the beneficial growth factor FGF21 (Fibroblast Growth Factor 21). We highlight for the first time that SGLT2 inhibition results in the upregulation of SGLT1 protein in the retina and that SGLT1 is significantly increased in the diabetic retina.
Blockade of SGLT2 activity with DAPA may reduce retinal microvascular lesions in our novel DR mouse model. In conclusion, our data demonstrates the exciting future potential of SGLT1 and/or SGLT2 inhibition as a therapeutic for DR.
糖尿病视网膜病变（DR）是全球失明的主要原因。已证实钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂对糖尿病患者具有心脏和肾脏保护作用。然而，其对DR的潜在有益作用研究较少。本研究的目的是确定在特征明确的DR小鼠模型和对照中，达格列净（DAPA）抑制SGLT2对DR的影响。
以25mg/kg/天的剂量通过饮用水给有糖尿病和无糖尿病的小鼠施用达格列净，持续8周。每周测量尿葡萄糖水平，并在第7周测试其对葡萄糖的反应。治疗8周后，在终末麻醉下采集眼组织。使用免疫荧光、免疫组织化学和电子显微镜技术评估视网膜血管系统和神经结构。
达格列净治疗的DR小鼠表现出代谢益处，表现为健康体重增加和明显的葡萄糖耐量。达格列净减少了视网膜微血管和神经异常的发展，增加了有益生长因子FGF21（成纤维细胞生长因子21）。我们首次强调，SGLT2抑制导致视网膜中SGLT1蛋白上调，且SGLT1在糖尿病视网膜中显著增加。
在我们新的DR小鼠模型中，用DAPA阻断SGLT2活性可能减少视网膜微血管病变。总之，我们的数据证明了抑制SGLT1和/或SGLT2作为DR治疗方法具有令人兴奋的未来潜力。
