Poricoic acid A activates AMPK to attenuate fibroblast activation and abnormal extracellular matrix remodelling in renal fibrosis.

Abstract

BACKGROUND:

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.

PURPOSE:

We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis.

STUDY DESIGN:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.

• Authors: Dan-Qian Chen, Yan-Ni Wang, Nosratola D Vaziri, Lin Chen, He-He Hu, Ying-Yong Zhao
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 72 Pg. 153232 (Jul 2020) ISSN: 1618-095X [Electronic] Germany
• PMID: 32460034 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier GmbH. All rights reserved.

Chemical References

• Smad3 Protein
• Smad3 protein, rat
• Transforming Growth Factor beta1
• Triterpenes
• poricoic acid A
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (chemistry, genetics, metabolism)
• Animals
• Case-Control Studies
• Cell Line
• Dose-Response Relationship, Drug
• Extracellular Matrix (drug effects, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Fibrosis
• Humans
• Kidney (drug effects, metabolism, pathology)
• Kidney Diseases (drug therapy, metabolism, pathology)
• Male
• Mice, Inbred BALB C
• Molecular Docking Simulation
• Rats, Sprague-Dawley
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Triterpenes (chemistry, pharmacology)
• Ureteral Obstruction (drug therapy, metabolism, pathology)