Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress-mediated Wnt/β-catenin pathway activation.

Abstract

Fenofibrate has been shown to have therapeutic effects on diabetic retinopathy (DR). Our previous studies demonstrated that the oxidative stress-activated Wnt/β-catenin pathway plays a pathogenic role in diabetic complications. In the present study, we evaluate the effect and mechanism of fenofibrate on regulating the oxidative stress-activated Wnt/β-catenin pathway by using the genetic type 1 diabetes model of C57BL/6J-Ins2Akita mice and high glucose (HG)-treated ARPE-19. Our results demonstrated that retinal phosphorylation of LRP6 and nuclear β-catenin were increased in C57BL/6J-Ins2Akita mice suggesting activation of Wnt/β-catenin signaling. Meanwhile, C57BL/6J-Ins2Akita showed upregulation of oxidant enzyme Nox4 and Nox2 and downregulation of antioxidant enzyme SOD1 and SOD2. All these alterations were reversed in C57BL/6J-Ins2Akita mice with fenofibrate treatment. Moreover, fenofibrate significantly ameliorated diabetes-induced retinal vascular leakage in C57BL/6J-Ins2Akita mice. In cultured ARPE-19, fenofibrate decreased HG-induced Nox2 and Nox4 upregulation, attenuated SOD1 and SOD2 downregulation and inhibited LRP6 phosphorylation. Moreover, activation of Wnt/β-catenin by Wnt3a conditional medium (WCM) reduced SOD1 and SOD2 and did not affect Nox2 and Nox4. Fenofibrate suppressed WCM-induced LRP6 phosphorylation and reversed SOD downregulation. Importantly, Nox4 overexpression directly phosphorylated LPR6 in ARPE19; conversely, Nox4 knockdown suppressed HG-induced LPR6 phosphorylation. Taken together, Nox-mediated oxidative stress contributes to Wnt/β-catenin activation in DR. Fenofibrate ameliorated DR through coordinate attenuation of oxidative stress and blockade of Wnt/β-catenin signaling.

• Authors: Qiuping Liu, Xian Zhang, Rui Cheng, Jian-Xing Ma, Jinglin Yi, Jingming Li
• Journal: Cell and tissue research (Cell Tissue Res) Vol. 376 Issue 2 Pg. 165-177 (May 2019) ISSN: 1432-0878 [Electronic] Germany
• PMID: 30610453 (Publication Type: Journal Article)

Chemical References

• Low Density Lipoprotein Receptor-Related Protein-6
• Lrp6 protein, mouse
• Superoxide Dismutase
• NADPH Oxidases
• Fenofibrate

Topics

• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (complications, genetics)
• Diabetes Mellitus, Type 1 (complications)
• Diabetic Retinopathy (drug therapy, etiology)
• Fenofibrate (pharmacology, therapeutic use)
• Low Density Lipoprotein Receptor-Related Protein-6 (metabolism)
• Mice
• Mice, Inbred C57BL
• NADPH Oxidases (metabolism)
• Oxidative Stress (drug effects)
• Superoxide Dismutase (metabolism)
• Wnt Signaling Pathway (drug effects)