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Isorhamnetin Alleviates Renal Fibrosis by Inducing Endogenous Hydrogen Sulfide and Regulating Thiol-Based Redox State in Obstructed Kidneys

Authors :
Zhen Zhang
Haiyan Zhang
Jianyu Shi
Zheng Wang
Yanni Liang
Jingao Yu
Hongbo Wang
Zhongxing Song
Zhishu Tang
Dongbo Zhang
Jian Yao
Source :
Biomolecules, Vol 14, Iss 10, p 1233 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H2S), we speculated that ISO may work through the induction of endogenous H2S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial–mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H2S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H2S production in vivo and in vitro. The elevated H2S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H2S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H2S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H2S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H2S, the H2S-inducing nature of ISO could be exploited to treat various diseases.

Details

Language :
English
ISSN :
2218273X
Volume :
14
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Biomolecules
Publication Type :
Academic Journal
Accession number :
edsdoj.198fe7d7973c4f63837a4d715799b5e8
Document Type :
article
Full Text :
https://doi.org/10.3390/biom14101233