High Glucose Promotes the Ferroptosis and Dysfunction of Endothelial Cells by Downregulating SLC3A2 and Promoting the Development of Nephropathy

TL;DR

High glucose causes endothelial cell dysfunction and ferroptosis, contributing to diabetic nephropathy, with SLC3A2 identified as a key regulator.

Contribution

Identifies SLC3A2 as a novel regulator linking high glucose, ferroptosis, and diabetic nephropathy.

Findings

High glucose exposure leads to endothelial dysfunction, ENDMT, and ferroptosis activation.

Reduced SLC3A2 expression correlates with increased inflammation, fibrosis, and ferroptosis.

A STAT1 inhibitor and antiferroptosis drug like fludarabine show potential in alleviating endothelial dysfunction.

Abstract

Background: Diabetic nephropathy, a leading cause of end-stage renal disease, is a major health concern. Its early-stage signs are unclear. Endothelial dysfunction, an early indicator, is suitable for early detection and intervention. However, current treatments mainly focus on glycemic and blood pressure control, lacking specific methods for targeting this dysfunction.

Method: We reanalyzed GSE13535 dataset, which has single-cell RNA-seq of high-glucose-exposed endothelial cells. HUVECs were cultured in high-glucose and TNF-α. We conducted RNA extraction, qPCR, western blotting, iron measurement, TUNEL assay, and bioinformatics analysis. An antiferroptosis drug was used in STZ-treated diabetic mice.

Results: Single-cell RNA-seq showed early endothelial cell dysfunction, along with ENDMT, cytokine release, and ferroptosis activation. SLC3A2 was identified as a key; its reduced expression was linked to more inflammation, fibrosis, and ferroptosis. Diabetic mice had low SLC3A2 and more ferroptosis in glomerular endothelial cells. A STAT1 inhibitor alleviated endothelial dysfunction.

Conclusion: Endothelial dysfunction and ferroptosis are crucial in diabetic nephropathy. Identifying SLC3A2 as a key regulator gives insights into potential treatments. Fludarabine shows promise. Further research on mechanisms and strategies is needed to improve patient outcomes.

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