Luteolin can ameliorate renal interstitial fibrosis-induced renal anaemia through the SIRT1/FOXO3 pathway

Abstract

Luteolin is a natural flavonoid exhibiting multiple pharmacological activities. Renal anaemia is an important complication of chronic kidney disease (CKD). Whether luteolin can ameliorate renal interstitial fibrosis-induced renal anaemia remains unclear. We examined the therapeutic effects of luteolin in in vitro and in vivo models of renal interstitial fibrosis-induced renal anaemia. After high-throughput sequencing analysis of animal samples, we screened differentially expressed genes (DEGs) associated with luteolin-mediated improvements, performed GO and KEGG functional and pathway enrichment analyses, and validated the mechanism in vitro and in vivo. In vivo, haemoglobin and haematocrit were increased significantly, blood urea nitrogen and creatinine were decreased significantly, and the degree of renal interstitial injury and fibrosis was significantly alleviated in luteolin-treated mice compared with model mice. Erythropoietin (EPO) and hypoxia inducible factor 2A (HIF2A) levels were significantly increased and alpha smooth muscle actin (α-SMA), collagen I (COLI) and fibronectin (FN) levels were significantly decreased. Transcriptomic analysis revealed significant increases in sirtuin 1 (SIRT1) and forkhead box O3 (FOXO3) after luteolin intervention; these effects were validated in vitro and in vivo. Combined treatment with luteolin and the SIRT1 activator resveratrol or the SIRT1 inhibitor sirtinol and SIRT1–siRNA transfection revealed that blocking SIRT1 reduced FOXO3 expression and significantly decreased the benefits of luteolin, while resveratrol had the opposite effects. Molecular docking analysis indicated a stable conformation between luteolin and SIRT1. In vitro and in vivo systematic and transcriptomic studies showed that luteolin attenuates renal anaemia caused by renal fibrosis through the SIRT1/FOXO3 pathway.