Angiotensin type 2 receptor activation limits kidney injury during the early phase and induces Treg cells during the late phase of renal ischemia

Abstract

Kidney infiltrating immune cells such as monocytes, neutrophils, and T cells play critical roles in renal ischemia-reperfusion (IR) injury and repair. Recently, the angiotensin II type 2 receptor (AT₂R) has been implicated in protecting kidneys against injury and monocyte infiltration, particularly in chronic kidney disease. However, the role of AT₂R in IR injury and repair phases and T cell modulation is unknown. To address this question, Sprague-Dawley rats were subjected to IR with or without AT₂R agonist C21 treatment. IR caused early (2 h postreperfusion) renal functional injury (proteinuria, plasma urea, and creatinine) and enhanced immune cells (T cells and CD4 T cells) infiltration and levels of the proinflammatory cytokines monocyte chemoattractant protein-1, TNF-α, and IL-6. C21 treatment reversed these changes but increased the anti-inflammatory IL-10 level. On day 3, C21 treatment increased CD4⁺FoxP3⁺ (regulatory T cells) and CD4⁺IL-10⁺ cells and reduced kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in the kidney compared with the IR control, suggesting the involvement of AT₂R in kidney repair. These data indicate that AT₂R activation protects the kidney against IR injury and immune cell infiltration in the early phase and modulates CD4 T cells toward the regulatory T cell phenotype, which may have long-term beneficial effects on kidney function.NEW & NOTEWORTHY The angiotensin II type 2 receptor agonist C21 has been known to have a renoprotective role in various kidney pathologies. C21 treatment (before renal ischemia) attenuated postischemic kidney injury, kidney dysfunction, and immune cell infiltration during the injury phase. Also, C21 treatment modulated the kidney microenvironment by enhancing anti-inflammatory responses mainly mediated by IL-10. During the repair phase, C21 treatment enhanced IL-10-secreting CD4 T cells and FoxP3-secreting regulatory T cells in Sprague-Dawley rats.

Keywords: C21; FoxP3; angiotensin II type 2 receptor; interleukin-10; ischemia-reperfusion injury.