Novel poricoic acids attenuate renal fibrosis through regulating redox signalling and aryl hydrocarbon receptor activation

Background: Renal fibrosis is the final manifestation of chronic kidney disease (CKD). Renal fibrosis is largely driven by oxidative stress and inflammation. Purpose: The aim of the current study was to identify novel poricoic acids from Poria cocos and investigated their antifibrotic effects and the underlying mechanism. Methods: In this study, we identified six novel poricoic acids from Poria cocos and examined their antifibrotic effect using transforming growth factor-beta 1- (TGF-beta 1-) induced cultured human kidney proximal tubular epithelial cells (HK-2) and mice with unilateral ureteral obstruction (UUO). Results: Treatment with six poricoic acids significantly inhibited TGF-beta 1-induced a-smooth muscle actin expression at both mRNA and protein levels in HK-2 cells. Three compounds with an intact carboxyl group at C-3 position showed a stronger inhibitory effect than that of other three compounds with esterified carboxyl group at the C-3 position. Mechanistically, poricoic acid ZM (PZM) and poricoic acid ZP (PZP) attenuate renal fibrosis through the modulation of redox signalling including the inhibition of proinflammatory nuclear factor kappa B (NF-kappa B) signalling and its target genes as well as the activation of antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) signalling and its downstream target gene in both TGF-beta 1-induced HK-2 cells and UUO mice. PZM treatment and PZP treatment inhibit the upregulated aryl hydrocarbon receptor and they target the gene expression in UUO mice. Intriguingly, PZM treatment exhibits a stronger inhibitory effect than that of the PZP treatment. Structure-function relationship reveals that the carboxyl group at C-3 position is the most important bioactive function group in secolanostane tetracyclic triterpenoids against renal fibrosis. Conclusions: PZM and PZP attenuated renal fibrosis through the modulation of redox signalling and the aryl hydrocarbon receptor signalling pathway. Our findings will provide several promising leading compounds against renal fibrosis.