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Dihydroquercetin protects against renal fibrosis by activating the Nrf2 pathway
Wei Wang1, Bei-Lei Ma2, Chang-Geng Xu3
1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Hefei 23022, China.
Background:
Dihydroquercetin (DHQ) is an antifibrotic agent. However, whether DHQ can prevent renal fibrosis remains unknown.
Purpose:
This study aimed to investigate the effects of DHQ on tubulointerstitial fibrosis and its underlying mechanisms in unilateral ureteral obstruction (UUO) mice in vivo and NRK-49F cells in vitro.
Methods:
In vivo, UUO mice received vehicle or DHQ treatment. In vitro, NRK-49F cells were pretreated with DHQ and exposed to transforming growth factor-β1 (TGF-β1). Changes in fibroblast activation, collagen synthesis, oxidative stress, and related signaling pathways were assessed by immunohistochemical staining, Western blot analysis, real-time reverse transcription-PCR, and fluorescence microscopy.
Results:
UUO induced tubular atrophy, inflammation, fibroblast differentiation into myofibroblast, and collagen deposition, whereas DHQ ameliorated these effects. UUO also resulted in decreased levels of nuclear factor-erythroid-2-related factor 2 (Nrf2), catalase, and heme oxygenase-1, but increased H2O2 and malondialdehyde levels. DHQ treatment corrected these changes. In vitro, the intracellular Nrf2 level of NRK-49F exposed to TGF-β1 decreased. However, DHQ rescued intracellular Nrf2 level and promoted nuclear translocation of Nrf2. DHQ scavenged TGF-β1-induced accumulation of reactive oxygen species, inhibited TGF-β1-induced Smad3 phosphorylation, and prevented TGF-β1-induced fibroblast activation and collagen synthesis in NRK-49F. Nrf2 knockdown could suppress the DHQ-mediated inhibitory effects on oxidative stress, Smad3 phosphorylation, fibroblast activation, and collagen deposition. Furthermore, DHQ ameliorated established renal fibrosis in UUO mice.
Conclusions:
DHQ posed remarkable preventive and therapeutic effects on UUO-induced renal fibrosis and suppressed fibroblast activation by reducing oxidative stress and Smad3 phosphorylation via Nrf2 signaling. This study provided a mechanistic basis for the clinical application of DHQ in renal fibrosis treatment.
Insights
Dihydroquercetin (DHQ) effectively prevents and treats kidney fibrosis by reducing oxidative stress and Smad3 phosphorylation through Nrf2 signaling. This antifibrotic agent shows promise for clinical applications in renal fibrosis.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Dihydroquercetin (DHQ) is recognized as an antifibrotic agent.
- The potential of DHQ in preventing renal fibrosis remains largely unexplored.
Purpose of the Study:
- To investigate the antifibrotic effects of DHQ on tubulointerstitial fibrosis.
- To elucidate the underlying mechanisms of DHQ action in unilateral ureteral obstruction (UUO) mouse models and NRK-49F cells.
Main Methods:
- In vivo studies utilized UUO mice treated with vehicle or DHQ.
- In vitro experiments involved NRK-49F cells pretreated with DHQ and exposed to TGF-β1.
- Assessed fibroblast activation, collagen synthesis, oxidative stress, and signaling pathways using immunohistochemistry, Western blot, RT-PCR, and fluorescence microscopy.
Main Results:
- DHQ ameliorated UUO-induced tubular atrophy, inflammation, and collagen deposition.
- DHQ treatment restored Nrf2 levels, reduced oxidative stress markers (H2O2, MDA), and increased antioxidant enzymes (catalase, HO-1).
- In vitro, DHQ inhibited TGF-β1-induced fibroblast activation, collagen synthesis, and Smad3 phosphorylation by enhancing Nrf2 nuclear translocation and scavenging reactive oxygen species.
Conclusions:
- DHQ demonstrates significant preventive and therapeutic effects against UUO-induced renal fibrosis.
- DHQ suppresses fibroblast activation by mitigating oxidative stress and Smad3 phosphorylation via the Nrf2 signaling pathway.
- This research provides a mechanistic foundation for the clinical use of DHQ in treating renal fibrosis.
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