Abstract
Purpose :
Disturbed microglial homeostasis and the consequent neuroinflammation contribute to the pathogenesis of diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological glial activation, remain to be elucidated. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism and energy homeostasis. The present study aimed to determine if PPARα affects pathological alterations of microglial function in DR.
Methods :
Global Pparα-/- mice, microglia-specific conditional Pparα knock out (PCKO) and transgenic (PCTG) mice were used. Diabetes was induced via intraperitoneal injections of streptozotocin (STZ, 55 mg/kg) at the age eight-to-ten weeks. Optical coherence tomography (OCT) imaging and electroretinogram (ERG) were assessed at 8 months of age. Retinae were collected and pericyte density was quantified following periodic acid-Schiff staining. Cultured Pparα-/- primary cells were treated with a diabetic stressor 4-HNE. The mitochondrial (Mito) stress assay and the Glycolytic Rate assay were assessed using a Seahorse XF Pro Extracellular Flux Analyzer.
Results :
In global Pparα-/- mice, retinal microglia exhibited decreased structural complexity and enlarged cell bodies (p<0.05), suggesting microglial activation. PCKO mice showed decreased retinal thickness as revealed by OCT (p<0.01). Under STZ-induced diabetes, diabetic PCKO mice exhibited decreased ERG response (p<0.0001), while diabetes-induced retinal dysfunction was alleviated in PCTG mice (p<0.0001). Additionally, diabetes-induced retinal pericyte loss was exacerbated in diabetic PCKO mice (p<0.05) and alleviated in diabetic PCTG mice (p<0.0001). In cultured microglial cells with the diabetic stressor 4-HNE, metabolic flux analysis demonstrated that Pparα ablation caused a metabolic shift from oxidative phosphorylation to glycolysis. Pparα deficiency also increased the expression of inflammatory regulator STING (p<0.001) and pro-inflammatory cytokine TNF-α (p<0.01) in microglia.
Conclusions :
Taken together, these findings revealed a critical role of microglial PPARα in pathological microgliosis, neurodegeneration, and vascular damage in DR, providing insight into the underlying molecular mechanisms of microgliosis in this context and suggesting microglial PPARα as a potential therapeutic target.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.