The intestinal flora serves a critical role in the development of hyperuricemia-induced chronic kidney disease (CKD). We previously found that natural flavonol fisetin exhibited nephroprotective effects in hyperuricemic mice. However, the mechanism remains largely unknown. To investigate the underlying mechanism of fisetin, mice were fed with potassium oxonate and adenine to introduce hyperuricemia-induced CKD. Fisetin improved kidney function, ameliorated renal fibrosis, and restored enteric dysbacteriosis in hyperuricemia-induced CKD mice. Meanwhile, gut microbiota-derived tryptophan metabolites, especially l-kynurenine, showed correlations with nephroprotective profiles of fisetin. Additionally, the kidney expression of the aryl hydrocarbon receptor (AHR), an endogenous receptor of l-kynurenine, was enhanced in hyperuricemic mice and further reduced in fisetin-treated mice. Finally, in vitro results showed that inhibition of AHR activation attenuated l-kynurenine-induced fibrosis. These results highlighted that fisetin protected against hyperuricemia-induced CKD via modulating gut microbiota-mediated tryptophan metabolism and AHR activation.
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