Downregulation of acylglycerol kinase suppresses high glucose-induced endothelial-mesenchymal transition in HRECs through regulating the LPAR1/TGF-β/Notch signaling pathway.

The endothelial-mesenchymal transition (EndMT) participates in the progression of diabetic retinopathy (DR), but cell-intrinsic factors modulating this process remain elusive. In this study, we explored the role of lysophosphatidic acid (LPA)-producing enzyme, acylglycerol kinase (AGK) in the EndMT of human retinal microvascular endothelial cells (HRECs) under high glucose (HG) conditions. We found that AGK was significantly elevated in HG-treated cells. In addition, AGK knockdown reversed the HG-induced EndMT in HRECs, which was evidenced by the increased epithelial markers (CD31 and VE-cadherin) and decreased mesenchymal markers (FSP1 and α-SMA). Furthermore, downregulation of AGK inhibited the HG-induced activation of TGF-β/Notch pathways, whereas exogenous TGF-β1 (10 ng/ml) impeded the inhibitory effects of AGK knockdown on HG-induced EndMT in HRECs. Additionally, the silence of AGK abolished the HG-induced upregulation of LPA and its receptor LPAR1, and overexpression of LPAR1 further rescued the AGK knockdown-mediated inhibition of the EndMT process. In conclusion, we demonstrate that downregulation of acylglycerol kinase suppresses high glucose-induced endothelial-mesenchymal transition in HRECs through regulating the LPAR1/TGF-β/Notch signaling pathway, indicating that AGK might be a potential therapeutic target for the treatment of DR.