HIF-1α/PPAR-γ/SIRT1 axis drives astrocyte senescence and regulates endothelial function via GDNF/NRTN in diabetic retinopathy

Background Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Astrocyte senescence is highly prevalent in DR, but the underlying regulatory mechanism remains unclear. This study aims to investigate the role of the HIF-1α/PPAR-γ/SIRT1 axis in regulating retinal astrocyte senescence and endothelial function in DR. Methods Mouse retinal astrocytes were exposed to high glucose (30 mM) to mimic diabetic conditions. Senescence was evaluated by β-galactosidase staining. Signaling pathways were manipulated using HIF-1α inhibitor (PX-478), PPAR-γ inhibitor (T0070907), SIRT1 agonist (SRT2104), and autophagy inhibitor (3-MA). Protein and mRNA levels of key factors were detected by Western blot and RT-qPCR. Astrocytes and retinal microvascular endothelial cells were co-cultured in Transwell systems to assess paracrine regulation on endothelial migration, proliferation, and apoptosis. Results High glucose induced astrocyte senescence, inflammatory activation, and downregulation of GDNF and NRTN, accompanied by elevated HIF-1α and PPAR-γ, and reduced SIRT1 expression and autophagy activity. Inhibiting HIF-1α or activating SIRT1 attenuated senescence, apoptosis, and inflammation, restored autophagy, and upregulated GDNF/NRTN secretion. HIF-1α negatively regulated SIRT1 expression via PPAR-γ. Senescent astrocytes impaired endothelial function through reduced GDNF/NRTN; overexpression of GDNF or NRTN in astrocytes preserved endothelial migration and proliferation, and inhibited apoptosis. Conclusion HIF-1α/PPAR-γ/SIRT1 axis mediates high glucose-induced astrocyte senescence via autophagy dysfunction. Senescent astrocytes disrupt retinal endothelial homeostasis by reducing GDNF/NRTN secretion. Targeting this axis may represent a novel neurovascular protective therapeutic strategy for DR.