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

Ming Wang; He-He Hu; Yuan-Yuan Chen; Lin Chen; Xia-Qing Wu; Ying-Yong Zhao

doi:10.1016/j.phymed.2020.153323

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

Phytomedicine. 2020 Dec:79:153323. doi: 10.1016/j.phymed.2020.153323. Epub 2020 Sep 1.

Authors

Ming Wang¹, He-He Hu¹, Yuan-Yuan Chen¹, Lin Chen¹, Xia-Qing Wu¹, Ying-Yong Zhao²

Affiliations

¹ Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an 710069, Shaanxi, China.
² Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an 710069, Shaanxi, China. Electronic address: zyy@nwu.edu.cn.

PMID: 32920287
DOI: 10.1016/j.phymed.2020.153323

Abstract

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-β1- (TGF-β1-) 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-β1-induced α-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-κB) 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-β1-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.

Keywords: Aryl hydrocarbon receptor; Poria cocos; Poricoic acid; Redox signalling; Renal fibrosis; Unilateral ureteral obstruction.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Cell Line
Fibrosis
Humans
Kidney / drug effects*
Kidney / pathology*
Kidney Diseases / drug therapy*
Kidney Diseases / metabolism
Kidney Diseases / pathology
Kidney Tubules, Proximal / cytology
Male
Mice, Inbred BALB C
Molecular Structure
NF-E2-Related Factor 2 / metabolism
NF-kappa B / metabolism
Oxidation-Reduction / drug effects
Receptors, Aryl Hydrocarbon / metabolism*
Signal Transduction / drug effects
Ureteral Obstruction / drug therapy
Ureteral Obstruction / genetics
Wolfiporia / chemistry

Substances

AHR protein, human
Basic Helix-Loop-Helix Transcription Factors
NF-E2-Related Factor 2
NF-kappa B
NFE2L2 protein, human
Receptors, Aryl Hydrocarbon