Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism
Background: Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mec...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Karger Publishers
2021-02-01
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| Series: | Kidney Diseases |
| Subjects: | |
| Online Access: | https://www.karger.com/Article/FullText/512986 |
| _version_ | 1818557340638511104 |
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| author | Qin Yang Li Gao Xiao-wei Hu Jia-nan Wang Yao Zhang Yu-hang Dong Hui Yao Lan Xiao-ming Meng |
| author_facet | Qin Yang Li Gao Xiao-wei Hu Jia-nan Wang Yao Zhang Yu-hang Dong Hui Yao Lan Xiao-ming Meng |
| author_sort | Qin Yang |
| collection | DOAJ |
| description | Background: Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Objectives: Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation. Methods: Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols – lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3. Results: Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy. Conclusions: These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI. |
| first_indexed | 2024-12-13T23:58:13Z |
| format | Article |
| id | doaj.art-028f7ecd29ae47a8ac3fab77ad1d0105 |
| institution | Directory Open Access Journal |
| issn | 2296-9381 2296-9357 |
| language | English |
| last_indexed | 2024-12-13T23:58:13Z |
| publishDate | 2021-02-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Kidney Diseases |
| spelling | doaj.art-028f7ecd29ae47a8ac3fab77ad1d01052022-12-21T23:26:28ZengKarger PublishersKidney Diseases2296-93812296-93572021-02-0111910.1159/000512986512986Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent MechanismQin YangLi GaoXiao-wei HuJia-nan WangYao ZhangYu-hang DongHui Yao LanXiao-ming MengBackground: Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Objectives: Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation. Methods: Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols – lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3. Results: Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy. Conclusions: These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI.https://www.karger.com/Article/FullText/512986acute kidney injurycisplatinsmad3nox4programmed cell deathinflammation |
| spellingShingle | Qin Yang Li Gao Xiao-wei Hu Jia-nan Wang Yao Zhang Yu-hang Dong Hui Yao Lan Xiao-ming Meng Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism Kidney Diseases acute kidney injury cisplatin smad3 nox4 programmed cell death inflammation |
| title | Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism |
| title_full | Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism |
| title_fullStr | Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism |
| title_full_unstemmed | Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism |
| title_short | Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism |
| title_sort | smad3 targeted therapy protects against cisplatin induced aki by attenuating programmed cell death and inflammation via a nox4 dependent mechanism |
| topic | acute kidney injury cisplatin smad3 nox4 programmed cell death inflammation |
| url | https://www.karger.com/Article/FullText/512986 |
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