The protective effects of a novel AT 2 receptor agonist, β-Pro 7 Ang 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: France 01.05.2023
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - prevention & control; Animals; Collagen - pharmacology; Kidney; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Reperfusion; Reperfusion Injury - genetics; Macrophage phenotype; Ischemia-reperfusion injury; Acute kidney injury; Fibrosis; Metalloproteinase; Macrophages; Renin-angiotensin system; ATR agonist
• ISSN: 1950-6007

This study investigated the reno-protective effects of a highly selective AT R agonist peptide, β-Pro Ang 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-Pro Ang 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-Pro Ang 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-Pro Ang 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-Pro Ang III treatment. FACS analysis showed a reduced number and proportion of CD45 CD11b F4/80 macrophages in IRI kidneys in response to β-Pro Ang 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-Pro Ang 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-Pro Ang 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.