Resveratrol protects against uremic serum-induced endothelial cell injury by activating the FUS/KLF2/FBXW7 signaling pathway

Abstract Background Chronic kidney disease causes endothelial cell dysfunction associated with uremia, which triggers a high risk of cardiovascular diseases. Furthermore, prolonged exposure of the vascular endothelium to uremic toxins could provoke endothelial damage in patients with end-stage renal disease. Resveratrol (RSV), a dietary polyphenol compound, has been reported to possess health benefits due to its anti-inflammatory and anti-oxidative properties. However, the role of RSV on uremic serum (US)-induced endothelial cell injury is still unclear. Methods HUVECs were stimulated by the US to mimic the inflammatory damage model in vitro. Cell viability and apoptosis were detected using CCK-8 and flow cytometry. IL-6, IL-1β, and TNF-α were evaluated using ELISA. ROS and SOD levels were detected using special assay kits. Kruppel-Like Factor 2 (KLF2), Fused-in-Sarcoma (FUS), and F-box and WD repeat domain-containing 7 protein (FBXW7) levels were determined using western blot. KLF2 mRNA level was examined using RT-qPCR. After ENCORI, HitPredict, and BioGRID software prediction, the interaction between KLF2 and FUS or FBXW7 was identified using RIP and Co-Immunoprecipitation (IP) assays. Results RSV could relieve US-triggered HUVEC viability inhibition, apoptosis, inflammatory response, and oxidative stress promotion. KLF2 knockdown partly attenuated the repression of RSV on US-induced HUVEC injury. Mechanistically, FUS bound with KLF2 to improve the stability of KLF2 mRNA. KLF2 interacted with FBXW7. RSV hindered US-caused HUVEC injury by regulating FUS/KLF2/FBXW7 pathway. Conclusion RSV exposure could mitigate US-evoked HUVEC dysfunction by activating the FUS/KLF2/FBXW7 pathway, providing a better understanding of the role of RSV in the anti-inflammatory therapeutics for uremia treatment.