poricoic-acid-a and Kidney-Diseases

Renal interstitial fibrosis is the common pathological process of various chronic kidney diseases to end-stage renal disease. Inhibition of fibroblast activation attenuates renal interstitial fibrosis. Our previous studies show that poricoic acid A (PAA) isolated from Poria cocos is a potent anti-fibrotic agent. In the present study we investigated the effects of PAA on renal fibroblast activation and interstitial fibrosis and the underlying mechanisms. Renal interstitial fibrosis was induced in rats or mice by unilateral ureteral obstruction (UUO). UUO rats were administered PAA (10 mg·kg

Topics: Animals; beta Catenin; Fibroblasts; Fibrosis; Kidney; Kidney Diseases; Mice; Molecular Docking Simulation; Rats; Signal Transduction; Sirtuin 3; Transforming Growth Factor beta1; Triterpenes; Ureteral Obstruction

In chronic kidney disease, although fibrosis prevention is beneficial, few interventions are available that specifically target fibrogenesis. Poricoic acid A (PAA) isolated from Poria cocos exhibits anti-fibrotic effects in the kidney, however the underlying mechanisms remain obscure.. We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis.. Unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (Nx) animal models and TGF-β1-induced renal fibroblasts (NRK-49F) were used to investigate the anti-fibrotic activity of PAA and its underlying mechanisms.. Western blots, qRT-PCR, immunofluorescence staining, co-immunoprecipitation and molecular docking methods were used. Knock-down and knock-in of adenosine monophosphate-activated protein kinase (AMPK) in the UUO model and cultured NRK-49F cells were employed to verify the mechanisms of action of PAA.. PAA improved renal function and alleviated fibrosis by stimulating AMPK and inhibiting Smad3 specifically in Nx and UUO models. Reduced AMPK activity was associated with Smad3 induction, fibroblast activation, and the accumulation and aberrant remodelling of extracellular matrix (ECM) in human renal puncture samples and cultured NRK-49F cells. PAA stimulated AMPK activity and decreased fibrosis in a dose-dependent manner, thus showing that AMPK was essential for PAA to exert its anti-fibrotic effects. AMPK deficiency reduced the anti-fibrotic effects of PAA, while AMPK overexpression enhanced its effect.. PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.

Topics: AMP-Activated Protein Kinases; Animals; Case-Control Studies; Cell Line; Dose-Response Relationship, Drug; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Diseases; Male; Mice, Inbred BALB C; Molecular Docking Simulation; Rats, Sprague-Dawley; Smad3 Protein; Transforming Growth Factor beta1; Triterpenes; Ureteral Obstruction