Hypoxia-Driven Angiopoietin Imbalance and Endothelial Dysfunction in Diabetic Kidney Disease

Background: Diabetic kidney disease (DKD) is a chronic condition in which glomerular endothelial cell injury contributes to filtration barrier dysfunction. In type 2 diabetes, metabolic stress and local hypoxia disrupt angiopoietin signaling, leading to endothelial instability. This study investigates hypoxia-induced changes in ANGPT1/2 expression and vascular responses to understand DKD pathophysiology, with a particular focus on targeting VE-PTP as a modulator of angiopoietin-Tie2 signaling. Methods: Chemical hypoxia was induced in HUVECs by CoCl2 treatment, and was confirmed by increased HIF-1α expression at both mRNA and protein levels. We then analyzed the expression of DKD-associated vascular regulators—ANGPT1, ANGPT2, Tie2, and VE-PTP—using qPCR, WB, and IF staining. In addition, we developed a nanoparticle delivery system designed to target VE-PTP-mediated pathways in hypoxia-induced endothelial cells. Results: CoCl2 treatment significantly increased HIF-1α expression, confirming successful hypoxic induction. Hypoxia altered the expression of angiogenic and endothelial regulatory genes, indicating activation of DKD-relataed pathways. These findings suggest that hypoxic conditions induce an angiopoietin imbalance and VE-PTP-mediated signaling. Initial application of the nanoparticle system demonstrated effective delivery to endothelial cells and modulation of pathway-specific targets, supporting its potential utility in DKD models. Conclusion: Using a hypoxia-induced HUVECs, we analyzed the expression of key vascular regulators involved in DKD. Our findings indicate that hypoxic conditions partially recapitulate endothelial dysfunction associated with DKD. This analysis provides foundational data to support further exploration of VE-PTP as potential therapeutic a target and contributes to a better understanding of endothelial mechanisms relevant to diabetic kidney disease.Schematic of VE-PTP–targeted nanoparticles in endothelial cells.