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Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway

Acta Pharmacologica Sinica volume 44, pages 2065–2074 (2023)Cite this article

Abstract

Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR−/−) mice. Diabetes was induced in LDLR−/− mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor β (TGFβ)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.

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Fig. 1: Fisetin improves STZ-impaired kidney function.
Fig. 2: Fisetin reduces collagen levels, while increases MMP2 and MMP9 expression in kidneys of diabetic LDLR−/− mice.
Fig. 3: Fisetin reduces AGEs and inflammatory cytokines in LDLR−/− mice kidneys.
Fig. 4: Fisetin improves renal fibrosis in diabetic LDLR−/− mice via reducing TGFβ1-CD36 pathway.
Fig. 5: Fisetin improves TGFβ-induced fibrosis through reducing PPARγ/CD36 signaling pathway in HK-2 cells.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) Grants 81973316 to JHH, the Major Special Science and Technology Project of Anhui Province (202003a07020015) to QSL, and the Open Fund of Tianjin Central Hospital of Gynecology Obstetrics/Tianjin Key Laboratory of Human Development and Reproductive Regulation (2021XHY01) to XXY.

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  1. These authors contributed equally: Ting-feng Zou, Zhi-gang Liu

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  1. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230601, China

    Ting-feng Zou, Zhi-gang Liu, Pei-chang Cao, Shi-hong Zheng, Wen-tong Guo, Tian-xiang Wang, Yuan-li Chen, Ya-jun Duan, Qing-shan Li, Chen-zhong Liao, Zhou-ling Xie, Ji-hong Han & Xiao-xiao Yang

  2. College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, 300071, China

    Ji-hong Han

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Contributions

XXY, TFZ, and ZGL performed study conception and design, and analyzed data. TFZ, ZGL, and PCC conducted the experiments. TFZ, ZGL, PCC, SHZ, WTG, and TXW performed the material preparation and interpretation. TFZ, ZGL, and XXY wrote the manuscript. XXY, YLC, YJD, QSL, CZL, ZLX, and JHH contributed reagents, analysis tools and revised the paper. All authors discussed the data and commented on the manuscript.

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Correspondence to Xiao-xiao Yang.

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Zou, Tf., Liu, Zg., Cao, Pc. et al. Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway. Acta Pharmacol Sin 44, 2065–2074 (2023). https://doi.org/10.1038/s41401-023-01106-6

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