The protective effects of a novel AT receptor agonist, β-ProAng III in ischemia-reperfusion kidney injury.

BACKGROUND AND PURPOSE

This study investigated the reno-protective effects of a highly selective ATR agonist peptide, β-ProAng 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-ProAng 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-ProAng 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-ProAng 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-ProAng III treatment. FACS analysis showed a reduced number and proportion of CD45CD11bF4/80 macrophages in IRI kidneys in response to β-ProAng 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-ProAng 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-ProAng 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.