Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials, Reagents, and Antibodies
2.2. Cell Culture
2.3. Animal Experiments
2.4. Cell Viability
2.5. Quantitative RT-PCR
2.6. Western Blotting (WB)
2.7. Immunofluorescence Assays
2.8. ROS and Hydrogen Peroxide (H2O2) Assays
2.9. NRF2 Knockdown
2.10. Coimmunoprecipitation (Co-IP)
2.11. Molecular Docking
2.12. Serum Biochemical Examination
2.13. HA Measurement
2.14. Histological and Immunohistochemical Analyses
2.15. Malondialdehyde and Antioxidant Enzyme Assays
2.16. Statistical Analyses
3. Results
3.1. HA Displays Strong Potential to Cause Fibrotic Responses In Vitro
3.2. TGFβ/SMAD Signaling Is Involved in HA-Induced Fibrotic Responses In Vitro
3.3. HA Induces Fibrotic Responses via ROS-Activated TGFβ/SMAD Signaling In Vitro
3.4. Effects of HA Treatment on the NRF2-Driven Antioxidant Pathway In Vitro
3.5. NRF2-Driven Antioxidant Network Mediates HA-Induced Fibrotic Responses In Vitro
3.6. HA Increases NRF2 Ubiquitination by Increasing E3 Ubiquitin Ligase Activity In Vitro
3.7. HA Promotes Renal Dysfunction and Fibrosis by Disrupting the Antioxidation Function of Nrf2 In Vivo
3.8. HA Induces Redox Imbalance by Disrupting the Antioxidation Function of Nrf2 In Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sun, B.; Wang, X.; Liu, X.; Wang, L.; Ren, F.; Wang, X.; Leng, X. Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease. Antioxidants 2020, 9, 783. https://doi.org/10.3390/antiox9090783
Sun B, Wang X, Liu X, Wang L, Ren F, Wang X, Leng X. Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease. Antioxidants. 2020; 9(9):783. https://doi.org/10.3390/antiox9090783
Chicago/Turabian StyleSun, Bowen, Xifan Wang, Xiaoxue Liu, Longjiao Wang, Fazheng Ren, Xiaoyu Wang, and Xiaojing Leng. 2020. "Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease" Antioxidants 9, no. 9: 783. https://doi.org/10.3390/antiox9090783