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- W3156173613 abstract "Autophagy deficiency plays a critical role in the pathogenesis of chronic kidney disease (CKD). AMP-activated protein kinase (AMPK), plays a central role in modulating metabolic stability. Several studies have shown that AMPK activator could ameliorate renal fibrosis, however, the underlying mechanisms have not been elucidated. In this study, we constructed a new AMPK activator, PA-S14, which is an allosteric compound from piericidin A (PA). The therapeutic effects of PA-S14 were tested in several CKD models. Furthermore, the autophagy status was also assessed. Bal/bc mice were performed unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) surgery, or injected with adriamycin (ADR). Some mice were intraperitoneally injected with PA-S14 (1mg/kg/d). In vitro, human renal tubular epithelial cells (HKC-8) were treated with transforming-growth factor (TGF)-β1, Bafilomycin A1(an autophagy inhibitor), and PA-S14. Kidney fibrosis, mitochondrial function, autophagy and AMPK/mTOR signaling pathway were assessed. Autophagosomes was visualized by the confocal microscopy after mRFP-EGFP-LC3 lentivirus infection and transmission electron microscopy. The expression of AMPK was decreased in various CKD models (UUO, 5/6 nephrectomy and adriamycin nephropathy). In vivo, administration of PA-S14 alleviated proteinuria and serum creatinine, and attenuated kidney fibrosis in unilateral ishemia-reperfusion (UIRI) and ADR mice. Moreover, PA-S14 upregulated p-AMPK expression and downregulated p-mTOR expression. PA-S14 also triggered the reversal of peroxisome proliferator-activated receptor γ co-activator 1 (PGC-1α), mitochondrial transcription factor A (TFAM), the important mitochondrial biogenesis factors. PA-S14 treatment also induced autophagosome formation, increased LC3-II lipidation, and decreased p62. In HKC-8 cells, PA-S14 inhibited TGF-β1-mediated fibrosis, alleviated the mitochondrial ROS production, and improved mitochondrial membrane potential. In addition, PA-S14 also activated AMPK and inhibited mTOR pathway, further leading to increased autophagic flux. In addition, Bafilomycin A1-suppressed autophagic flux could be reversed by PA-S14. PA-S14 also preserved the expression of phosphorylated AMPK in PP2C, an AMPK inhibitor, -treated cells. In summary, our results demonstrate that PA-S14 acts as a new AMPK activator to protect against renal fibrosis. The underlying mechanisms are related to PA-S14-induced AMPK activation, which further promotes autophagy through regulating mTOR pathway." @default.
- W3156173613 created "2021-04-26" @default.
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- W3156173613 date "2021-04-01" @default.
- W3156173613 modified "2023-09-26" @default.
- W3156173613 title "POS-382 A New AMPK Activator PA-S14 Attenuates Renal Injury through Promoting Autophagy" @default.
- W3156173613 doi "https://doi.org/10.1016/j.ekir.2021.03.400" @default.
- W3156173613 hasPublicationYear "2021" @default.
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