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

摘要

Fenofibrate has been shown to have therapeutic effects on diabetic retinopathy (DR). Our previous studies demonstrated that the oxidative stress-activated Wnt/-beta 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/-beta catenin pathway by using the genetic type 1 diabetes model of C57BL/6J-Ins2(Akita) mice and high glucose (HG)-treated ARPE-19. Our results demonstrated that retinal phosphorylation of LRP6 and nuclear beta-catenin were increased in C57BL/6J-Ins2(Akita) mice suggesting activation of Wnt/-beta catenin signaling. Meanwhile, C57BL/6J-Ins2(Akita) showed upregulation of oxidant enzyme Nox4 and Nox2 and downregulation of antioxidant enzyme SOD1 and SOD2. All these alterations were reversed in C57BL/6J-Ins2(Akita) mice with fenofibrate treatment. Moreover, fenofibrate significantly ameliorated diabetes-induced retinal vascular leakage in C57BL/6J-Ins2(Akita) 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/-beta 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/-beta catenin activation in DR. Fenofibrate ameliorated DR through coordinate attenuation of oxidative stress and blockade of Wnt/-beta catenin signaling.