The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury
Background and purpose: This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). Methods: C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S075333222300344X |
| _version_ | 1797857696283623424 |
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| author | Tingfang Zhang Yifang Li Andrea F. Wise Ketav Kulkarni Marie-Isabel Aguilar Chrishan S. Samuel Mark Del Borgo Robert E. Widdop Sharon D. Ricardo |
| author_facet | Tingfang Zhang Yifang Li Andrea F. Wise Ketav Kulkarni Marie-Isabel Aguilar Chrishan S. Samuel Mark Del Borgo Robert E. Widdop Sharon D. Ricardo |
| author_sort | Tingfang Zhang |
| collection | DOAJ |
| description | Background and purpose: This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). Methods: C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-Pro7Ang III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-Pro7Ang III with macrophage number and phenotype was determined in vivo and in vitro. Key results: Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to β-Pro7Ang III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-Pro7Ang III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)− 6 production but increased IL-10 secretion, compared to LPS alone. Conclusion: Administration of β-Pro7Ang III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI. |
| first_indexed | 2024-04-09T21:00:59Z |
| format | Article |
| id | doaj.art-8f09833c4fcb4a20a16d01c85cdadc4a |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-09T21:00:59Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-8f09833c4fcb4a20a16d01c85cdadc4a2023-03-29T09:24:23ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-05-01161114556The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injuryTingfang Zhang0Yifang Li1Andrea F. Wise2Ketav Kulkarni3Marie-Isabel Aguilar4Chrishan S. Samuel5Mark Del Borgo6Robert E. Widdop7Sharon D. Ricardo8Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, AustraliaDepartment of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Correspondence to: Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 9 Ancora Imparo Way, Clayton, VIC 3800, Australia.Background and purpose: This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). Methods: C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-Pro7Ang III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-Pro7Ang III with macrophage number and phenotype was determined in vivo and in vitro. Key results: Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to β-Pro7Ang III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-Pro7Ang III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)− 6 production but increased IL-10 secretion, compared to LPS alone. Conclusion: Administration of β-Pro7Ang III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.http://www.sciencedirect.com/science/article/pii/S075333222300344XAT2R agonistAcute kidney injuryIschemia-reperfusion injuryMacrophagesFibrosisMetalloproteinase |
| spellingShingle | Tingfang Zhang Yifang Li Andrea F. Wise Ketav Kulkarni Marie-Isabel Aguilar Chrishan S. Samuel Mark Del Borgo Robert E. Widdop Sharon D. Ricardo The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury Biomedicine & Pharmacotherapy AT2R agonist Acute kidney injury Ischemia-reperfusion injury Macrophages Fibrosis Metalloproteinase |
| title | The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury |
| title_full | The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury |
| title_fullStr | The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury |
| title_full_unstemmed | The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury |
| title_short | The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury |
| title_sort | protective effects of a novel at2 receptor agonist β pro7ang iii in ischemia reperfusion kidney injury |
| topic | AT2R agonist Acute kidney injury Ischemia-reperfusion injury Macrophages Fibrosis Metalloproteinase |
| url | http://www.sciencedirect.com/science/article/pii/S075333222300344X |
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