Work

Suppression of HIF-1α alleviates the symptoms associated with diabetic retinopathy in mice

Year: 2025

Type: article

Abstract: Retinal hypoxia is a critical driver of blinding retinal vascular diseases like diabetic retinopathy (DR). This study aims to investigate the role and associated molecular mechanisms of hypoxia-inducing factor 1-α (HIF-1α) in mice with DR. Streptozotocin (STZ) was utilized to induce diabetic mouse models. Retinal structure and vasculature were assessed by Hematoxylin and Eosin (H&E) staining and Fundus Fluorescein Angiography (FFA). We analyzed key protein expression in retinal tissues via Western blot. Mice induced by STZ were treated with PX-478 (an inhibitor of HIF-1α), and Evans Blue staining was performed to assess the impact of HIF-1α depletion on blood-retinal barrier (BRB) function. Transmission electron microscopy (TEM) was used to observe autophagy in retinal tissue cells. H&E staining and FFA confirmed the successful establishment of the DR mouse model. In STZ-induced diabetic mice, we observed significant up-regulation of HIF-1α and the cellular senescence makers p16 and p21, alongside impaired autophagy. Furthermore, protein levels of the neuroprotective factors Glial cell line-derived neurotrophic factor (GDNF), and neurturin (NRTN), as well as sirtuin 1 (SIRT1), were decreased, while peroxisome proliferator-activated receptor-gamma (PPAR-γ) was increased. Following treatment with PX-478, the decreasing trend of GDNF, NRTN, microtubule-associated protein 1 light chain 3 B (LC3B), and SIRT1 protein levels was blocked, and the overexpression of HIF-1α, p16, p21, and PPAR-γ was inhibited. Additionally, PX-478 improved the barrier integrity of BRB in DR mice, and TEM showed an increase in autolysosomes in retinal tissues. This study demonstrates the significant role of HIF-1α in DR pathogenesis, providing a theoretical foundation for further exploration of HIF-1α-directed therapies for this sight-threatening complication of diabetes.

Source: Experimental Eye Research

DOI: 10.1016/j.exer.2025.110741