DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells
Abstract The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1–7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1–7)/MasR axis. However, due to th...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Veterinary Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13567-022-01122-0 |
| _version_ | 1811179178041540608 |
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| author | Xiangjun Zhang Fang Jia Weiwu Ma Xueqiang Li Xuezhang Zhou |
| author_facet | Xiangjun Zhang Fang Jia Weiwu Ma Xueqiang Li Xuezhang Zhou |
| author_sort | Xiangjun Zhang |
| collection | DOAJ |
| description | Abstract The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1–7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1–7)/MasR axis. However, due to the reported toxicity of DA, its application has been limited. In the current study, we synthesized a low toxicity DA derivative 3 (DAD3) and sought to determine whether DAD3 can also activate ACE2 in bovine mammary epithelial cells (BMEC) and regulate the RAS system to inhibit inflammation. We found that both DA and DAD3 can activate and promote ACE2 expression in BMEC. iRNA-mediated knockdown of ACE2 demonstrated that DAD3 activates the ACE2/Ang-(1–7)/MasR axis and plays an anti-inflammatory role in BMEC. Furthermore, the inhibitory effects of DA and DAD3 on the protein phosphorylation of MAPK and NF-κB pathways were reduced in ACE2-silenced BMEC. Our findings show that ACE2 is a target of DAD3, which leads to inhibition of the MAPK and NF-κB signalling pathways and protects against LPS-induced inflammation in BMEC. Thus, DAD3 may provide a new strategy to treat dairy cow mastitis. |
| first_indexed | 2024-04-11T06:30:25Z |
| format | Article |
| id | doaj.art-44e8d279a0374791a7d3a4fb0ae9a4a0 |
| institution | Directory Open Access Journal |
| issn | 1297-9716 |
| language | English |
| last_indexed | 2024-04-11T06:30:25Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Veterinary Research |
| spelling | doaj.art-44e8d279a0374791a7d3a4fb0ae9a4a02022-12-22T04:40:05ZengBMCVeterinary Research1297-97162022-12-0153111310.1186/s13567-022-01122-0DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cellsXiangjun Zhang0Fang Jia1Weiwu Ma2Xueqiang Li3Xuezhang Zhou4Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia UniversityKey Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia UniversityKey Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia UniversityKey Laboratory of Energy Sources and Chemical Engineering, Development Center of Natural Products and Medication and School of Chemistry and Chemical Engineering, Ningxia UniversityKey Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia UniversityAbstract The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1–7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1–7)/MasR axis. However, due to the reported toxicity of DA, its application has been limited. In the current study, we synthesized a low toxicity DA derivative 3 (DAD3) and sought to determine whether DAD3 can also activate ACE2 in bovine mammary epithelial cells (BMEC) and regulate the RAS system to inhibit inflammation. We found that both DA and DAD3 can activate and promote ACE2 expression in BMEC. iRNA-mediated knockdown of ACE2 demonstrated that DAD3 activates the ACE2/Ang-(1–7)/MasR axis and plays an anti-inflammatory role in BMEC. Furthermore, the inhibitory effects of DA and DAD3 on the protein phosphorylation of MAPK and NF-κB pathways were reduced in ACE2-silenced BMEC. Our findings show that ACE2 is a target of DAD3, which leads to inhibition of the MAPK and NF-κB signalling pathways and protects against LPS-induced inflammation in BMEC. Thus, DAD3 may provide a new strategy to treat dairy cow mastitis.https://doi.org/10.1186/s13567-022-01122-0Diminazene aceturatediminazene aceturate derivativebovine mammary epithelial cellsangiotensin-converting enzyme 2inflammation |
| spellingShingle | Xiangjun Zhang Fang Jia Weiwu Ma Xueqiang Li Xuezhang Zhou DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells Veterinary Research Diminazene aceturate diminazene aceturate derivative bovine mammary epithelial cells angiotensin-converting enzyme 2 inflammation |
| title | DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells |
| title_full | DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells |
| title_fullStr | DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells |
| title_full_unstemmed | DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells |
| title_short | DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells |
| title_sort | dad3 targets ace2 to inhibit the mapk and nf κb signalling pathways and protect against lps induced inflammation in bovine mammary epithelial cells |
| topic | Diminazene aceturate diminazene aceturate derivative bovine mammary epithelial cells angiotensin-converting enzyme 2 inflammation |
| url | https://doi.org/10.1186/s13567-022-01122-0 |
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