An integrated network pharmacology and cell metabolomics approach to reveal the role of rhein, a novel PPARα agonist, against renal fibrosis by activating the PPARα-CPT1A axis.
Phytomedicine
; 102: 154147, 2022 Jul 20.
Article
in En
| MEDLINE
| ID: mdl-35567992
ABSTRACT
BACKGROUND:
Rhein, an anthraquinone compound, displays extensive antifibrotic effects; however, its potential mechanisms are not fully understood. In this study, we explored the underlying molecular mechanism of action of rhein.METHOD:
An integrated network pharmacology and cell metabolomics approach was developed based on network pharmacology and bioinformatics method, and then successfully applied to speculate the potential targets of rhein and construct a rhein-target-metabolic enzyme-metabolite network. Thereafter, the antifibrotic mechanism of rhein was validated in TGF-ß- and oleic acid- induced HK-2 and NRK-52E cells in vitro as well as a unilateral ischemia-reperfusion injury Sprague-Dawley rat model.RESULTS:
Based on the construction of the rhein-target-metabolic enzyme-metabolite network, we found that rhein played an antifibrotic role through the PPAR-α-CPT1A-l-palmitoyl-carnitine axis. In vitro experiments demonstrated that rhein effectively activated the expression of PPARα and its downstream proteins (CPT1A and ACOX1) to alleviate lipid accumulation and fibrosis development. In vivo experiments indicated that rhein attenuated renal fibrosis mainly by activating the fatty acid oxidation pathway and improving lipid metabolism.CONCLUSION:
Taken together, our findings reveal that rhein is a novel agonist of PPARα, which contributes to its renoprotection through the regulation of the PPARα-CPT1A axis. Moreover, our study provides a novel insight into an integrated network pharmacology-metabolomics strategy for uncovering the pharmacological mechanisms of drugs from the system perspective.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
PPAR alpha
/
Kidney Diseases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Phytomedicine
Journal subject:
TERAPIAS COMPLEMENTARES
Year:
2022
Document type:
Article
Affiliation country:
China