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Bumetanide-blocked SLC12A2 exerts a protective effect in experimental diabetic retinopathy
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DOI：10.3892/ijmm.2026.5774.png)
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Abstract
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Diabetic retinopathy (DR) is a common microvascular complication that leads to vision loss in patients with diabetes. The SLC12A2/SLC12A4 inhibitor, bumetanide, has been reported to alleviate hypoxia-induced retinopathy. It was hypothesized that it may exert the same effect in DR. DR cell types and SLC12A2/SLC12A4 expression at the cell level were analyzed using single cell RNA-sequencing (scRNA-seq) data. Next, cell [high glucose (HG) stimulation] and animal (mice injected with streptozotocin) DR models were constructed. The protective effects and possible mechanisms of bumetanide and SLC12A2 were investigated through a series of experiments, including Cell Counting Kit-8, TUNEL, Transwell, tube formation, ELISA, immunofluorescence staining, western blot and reverse transcription-quantitative PCR assays. Bumetanide reduced HG-induced cell apoptosis by suppressing the expression of SLC12A2 and SLC12A4. Second, scRNA-seq analysis revealed that SLC12A2 was predominantly expressed in endothelial cells, which are the main targets of hyperglycemic damage. Endothelial cell-related markers were involved in angiogenesis and adhesion molecule-related pathways. Third, in HG-stimulated cells, SLC12A2 knockdown efficiently reduced the inflammatory response and angiogenesis, while maintaining endothelial barrier integrity. This protective process involved reduced release of inflammatory factors (IL-1 beta and IL-6) and growth factors (vascular endothelial growth factor), suppression of adhesion molecule expression (VCAM1, ICAM1, E-Selectin and P-Selectin), activation of tight junction protein (ZO-1), and decreased matrix metalloproteinases (MMP2 and MMP9). Furthermore, SLC12A2 deficiency ameliorated DR progression in streptozotocin-induced diabetic mice by improving retinal thickness and pathological changes. The present study elucidates the crucial role of bumetanide in DR treatment and suggests that targeting SLC12A2 may represent a novel therapeutic strategy for the prevention of DR.
Keywords:
diabetic retinopathy
bumetanide
single-cell transcriptomics
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