Background: Fluorofenidone (AKF-PD) is a novel pyridone agent and has potent anti-NLRP3 inflammasome and anti-fibrotic activities. However, the mechanisms underlying its pharmacological actions are not fully understood.
Methods: A renal fibrosis rat model was established by the unilateral ureteral obstruction (UUO) procedure and the rats were randomized and treated with, or without, AKF-PD for 3 and 7 days. The levels of renal fibrosis, NLRP3 inflammasome activation, mitochondrial function, and autophagy were tested in rat kidney tissues. Macrophages following lipopolysaccharides (LPS) and adenosine 5'-triphosphate (ATP) stimulation were examined by Western blot, spectrophotometry, and TEM.
Results: Compared with the untreated UUO rats, AKF-PD treatment significantly mitigated the UUO procedure-induced renal fibrosis in rats. AKF-PD treatment decreased mitochondrial dysfunction and IL-Iβ and caspase-1 expression in rat kidney tissues and reduced mitochondrial reactive oxygen species production in activated macrophages. Mechanistically, AKF-PD treatment significantly attenuated the PI3K/AKT/mTOR signaling, increased Beclin-1 and LC3 II expression and autophagosome formation, and ameliorated the mitochondrial damage in renal tissues and activated macrophages.
Conclusion: The results indicated that AKF-PD treatment inhibited renal interstitial fibrosis by regulating the autophagy-mitochondria-NLRP3 inflammasome pathway.
Keywords: AKF-PD; Autophagy; Mitochondrial dysfunction; NLRP3 inflammasome; Renal interstitial fibrosis.
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.