Diabetic retinopathy (DR) remains a major cause of blindness among diabetes mellitus patients. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel adipokine which is associated with multiple types of metabolism. Nevertheless, little is known about the role of CTRP3 in high glucose (HG)-induced human retinal pericytes (HRPs). This study set out to assess the influence of CTRP3 on HG-induced HRPs and elucidate the latent regulatory mechanism. RT-qPCR and Western blot were to analyze CTRP3 and forkhead box O4 (FOXO4) expression. Western blot was also utilized to detect the protein levels of apoptosis-related factors and nuclear factor erythroid 2-related factor 2 (Nrf2)/Nuclear factor-kappaB (NF-κB) signaling-related factors. CCK-8 was to measure cell proliferation while TUNEL assay was to estimate cell apoptosis. Levels of oxidative stress biomarkers including manganese (MnSOD), catalase (CAT) and malonedialdehyde (MDA) were evaluated by the corresponding kits. JASPAR database, ChIP and luciferase reporter assay were to verify the interaction between FOXO4 and CTRP3 promoter. The experimental results uncovered that CTRP3 expression was decreased in HG-stimulated HRPs. Moreover, CTRP3 overexpression strengthened the viability while abrogated the apoptosis and oxidative stress of HG-induced HRPs. Furthermore. FOXO4 was up-regulated in HG-induced HRPs. Besides, FOXO4 bond to CTRP3 promoter and inhibited CTRP3 transcription to modulate the Nrf2/NF-κB signaling pathway. FOXO4 up-regulation reversed the influence of CTRP3 elevation on the proliferation, apoptosis and oxidative stress of HG-induced HRPs. To be summarized, CTRP3 negatively modulated by FOXO4 prevented HG-induced oxidative damage in DR via modulation of Nrf2/NF-κB signaling.
Keywords: CTRP3; FOXO4; Human retinal pericytes; nrf2/NF-κB signaling; oxidative stress.