The protective effects of a novel AT2 receptor agonist, β-Pro7Ang III in ischemia-reperfusion kidney injury - 28/03/23
Abstract |
Background and purpose |
This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, 
-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 
-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 
-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 
-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 
-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to 
-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-
(TNF-
) and interleukin (IL)− 6 production but increased IL-10 secretion, compared to LPS alone.
Conclusion |
Administration of 
-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.
Abbreviations : ACEi, AKI, ARB, AT1R, AT2R, CKD, ESRD, FACS, FMO, GFR, IRI, IL, LPS, MMP, RAS, TNF-α
Keywords : AT2R agonist, Acute kidney injury, Ischemia-reperfusion injury, Macrophages, Fibrosis, Metalloproteinase, Macrophage phenotype, Renin-angiotensin system
Plan
-Pro7Ang III on the kidneys of IRI mice
-Pro7Ang III on F4/80+ macrophage infiltration and type IV collagen deposition in the kidneys of IRI mice
-Pro7Ang III on collagen I and III accumulation in the kidneys of IRI mice
-Pro7Ang III on the activity of gelatinase A (MMP-2) in the kidneys of IRI mice at day 7 post-injury
-Pro7Ang III on the macrophage gene expression profiles in the kidneys of IRI mice at either day 3 or day 7 post-injury
-Pro7Ang III cytokine production in THP-1 macrophages
Vol 161
Article 114556- mai 2023 Retour au numéro
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