Fluorofenidone attenuates renal fibrosis by inhibiting the mtROS-NLRP3 pathway in a murine model of folic acid nephropathy

• Published in: Biochemical and biophysical research communications Vol. 534; pp. 694 - 701
• Main Authors: Liao, Xiaohua, Jiang, Yupeng, Dai, Qin, Yu, Yue, Zhang, Yan, Hu, Gaoyun, Meng, Jie, Xie, Yanyun, Peng, Zhangzhe, Tao, Lijian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021
• Subjects: AKF-PD; Animals; Disease Models, Animal; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Fibrosis; Folic Acid - toxicity; Inflammasomes - drug effects; Inflammasomes - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - pathology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - pathology; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial damage; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Pyridones - pharmacology; Reactive Oxygen Species - metabolism; Renal fibrosis; AKF-PD; NLRP3; Renal fibrosis; Mitochondrial damage
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.11.017

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-β (TGF-β), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1β, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.
•The study firstly found that fluorofenidone improved kidney function and suppressed the deposition of ECM in the murine model, following administration to mice after 7 days of folic acid injection.•Fluorofenidone suppressed NLRP3 inflammasome activation by reducing mtROS.•Fluorofenidone can inhibit renal fibrosis by reducing mitochondrial damage and suppressing the downstream activation of the NLRP3 inflammasome in the folic acid nephropathy model.