American Diabetes Association
Browse

The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium-Glucose Transporter 2 Inhibitors

Download (860.37 kB)
figure
posted on 2024-04-12, 21:03 authored by Mayumi Yamato, Nao Kato, Ken-ichi Yamada, Toyoshi Inoguchi

The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we investigated the early pathogenic alterations in DR using streptozotocin-induced diabetic mice and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study, both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2i may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.

Funding

This work was partly supported by research funds from Taisho Pharmaceutical Co., Ltd. and Astellas Pharma Inc. This work was supported in part by an AMED-CREST grant (JP22gm0910013 to KY), JSPS KAKENHI grants (23H05481, 22H05572, and 20H00493 to KY), Takeda Science Foundation to KY. This work was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research from the AMED. The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

History

Usage metrics

    Diabetes

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC