The Role of HIF1α-PFKFB3 pathway in Diabetic Retinopathy.
Diabetic retinopathy (DR) is the leading cause of blindness in adults of developed countries. Both microvasculopathy and neurodegeneration are implicated in mechanisms of DR development, with neuronal impairment preceding microvascular abnormalities, which is often underappreciated in the clinic. Most current therapeutic strategies, including anti-vascular endothelial growth factor (anti-VEGF)- antibodies, aim at treating the advanced stages (diabetic macular oedema and proliferative diabetic retinopathy) and fail to target the neuronal deterioration. Hence, new therapeutic approach(es) intended to address both vascular and neuronal impairment are urgently needed. Hypoxia-inducible factor 1α (HIF1α) – 6-phosphofructo-2-kinase – fructose-2,6-bisphosphatase 3 (PFKFB3) pathway is critically implicated in the islet pathology of diabetes. Recent evidence highlighted the pathway relevance for pathologic angiogenesis and neurodegeneration, two key aspects in the diabetic retinopathy complication. PFKFB3 is a key to the sprouting angiogenesis along with VEGF by determining the endothelial tip-cell competition. Also, PFKFB3-driven glycolysis compromises the anti-oxidative capacity of neurons leading to neuronal loss and reactive gliosis. Therefore, the HIF1α-PFKFB3 signalling pathway is unique as being a pervasive pathological component across multiple cell types in the retina in the early as well as late stages of DR. A metabolic point-of-intervention based on HIF1α-PFKFB3 targeting thus deserves further consideration in DR.
Authors: Jie Min, Tianshu Zeng, Margaretha Roux, David Lazar, Lulu Chen, Slavica Tudzarova