The role of PPARβ/δ in diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is disease of microvascular complications and is a leading cause of blindness in working age adults. DR consists of two main stages: the early non-proliferative stage is driven primarily by inflammation while the later proliferative stage is characterized by pre-retinal neovascularization. The peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is a transcription factor with known functions in lipid metabolism and glucose homeostasis. The role of PPARβ/δ in inflammation and angiogenesis, however, is not yet defined. To determine the action of PPARβ/δ in processes related to DR, rna-sequencing was first used to evaluate the effect of the PPARβ/δ antagonist GSK0660 on TNFα-induced inflammation in retinal endothelial cells. It was discovered that GSK0660 regulates TNFα-induced chemokine expression and subsequent leukocyte adhesion to endothelial monolayers via a mechanism involving inhibition of both ERK activation and NF-κB translocation. Further studies determined activation of PPARβ/δ with the agonist GW0742 increased expression of the angiogenic protein ANGPTL4 from retinal cells, increased endothelial cell tube formation, and promoted retinal neovascularization. GSK0660 was anti-angiogenic as it reduced expression of ANGPTL4 from retinal cells, inhibited endothelial cell proliferation and tube formation, and ultimately mitigated retinal neovascularization. Taken together, inhibition of PPARβ/δ was both anti-inflammatory and anti-angiogenic, resulting in reduced chemokine secretion, leukostasis, and retinal angiogenesis.