The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury

• Published in: Biomedicine & pharmacotherapy Vol. 161; p. 114556
• Main Authors: Zhang, Tingfang, Li, Yifang, Wise, Andrea F., Kulkarni, Ketav, Aguilar, Marie-Isabel, Samuel, Chrishan S., Del Borgo, Mark, Widdop, Robert E., Ricardo, Sharon D.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.05.2023; Elsevier
• Subjects: Acute kidney injury; AT2R agonist; Fibrosis; Ischemia-reperfusion injury; Macrophage phenotype; Macrophages; Metalloproteinase; Renin-angiotensin system; ESRD; IRI; IL; RAS; AT2R agonist; Acute kidney injury; FMO; AT1R; FACS; Macrophages; Renin-angiotensin system; AT2R; LPS; Macrophage phenotype; ARB; MMP; GFR; Ischemia-reperfusion injury; TNF-α; Fibrosis; ACEi; Metalloproteinase; CKD; AKI
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114556

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). 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. 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. 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.