Abstract
Abstract Background and Aims Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. However, the versatile role and potential mechanism of fisetin against fibrotic kidney disease have not been well characterized. Recently, tubular ferroptosis contributes to the pathogenesis of CKD with a persistent inflammatory and profibrotic response. Method Here, we found that fisetin significantly improved tubular injury, inflammation, and tubulointerstitial fibrosis in adenine diet- and unilateral ureteral obstruction (UUO)-induced CKD mice. The renoprotective effects of fisetin were also confirmed to suppress inflammatory response and fibrogenesis in adenine- or TGF-β1-stimulated tubular epithelial cells. Results Mechanistically, fisetin inhibited ferroptosis in the kidneys of CKD mice as well as in injured tubular epithelial cells, as evidenced by a decrease of ACSL4, COX2, HMGB1, and an increase of GPX4. Meanwhile, fisetin effectively restored ultrastructural abnormalities of mitochondrial morphology and relieved the elevated iron, the downregulated GSH and GSH/GSSG, as well as the upregulated lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormal expression of ferroptosis key marker ACSL4 was verified in renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) and mice (adenine and UUO), which was also observed in injured tubular cells. Furthermore, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammation, and anti-fibrosis of fisetin in injured tubular cells. Conclusion In summary, we for the first time explored a novel aspect of fisetin via inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.
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