Frontiers in pharmacology · 2026
AT2R activation reduces M1-type macrophages and promotes tregs accumulation in ischemia-reperfusion-induced acute kidney injury.
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Ali Riyasat, Faisal Tahmid, Kulkarni Kalyani, Patel Sanket, Hussain Tahir
Аннотация
INTRODUCTION: Acute kidney injury (AKI) is marked by infiltration of immune cells, particularly macrophages and T cells, and their expansion as inflammatory and anti-inflammatory mediators to create a microenvironment critical for kidney injury/repair. As the angiotensin type 2 receptor (AT2R) is emerging as reno-protective and anti-inflammatory, this study aimed to analyze the phenotypes of macrophages and helper T cells (CD4) in response to AT2R activation in ischemia-reperfusion (IR)-induced AKI.
METHODS: Sprague Dawley rats were subjected to 30 min IR without and with AT2R agonist C21 administration. Rats were euthanized at 2 h, 3 d, and 5 d post IR. Flow cytometry of kidney digested cells was performed to analyze kidney infiltrating immune cells. For in-vitro polarization, mouse CD4 T cells were cultured in presence of various stimulus and characterized by flow cytometry and western blot analysis.
RESULTS: On day 3, there was a massive increase in macrophage/monocytes (CD68+) and M1 (CD68+CD86+) cell accumulation and a modest increase in M2 (CD68+CD163+) cell accumulation. The AT2R activation reduced CD68+ and M1 cells accumulation without affecting M2. Accumulation of CD4+CD25+ cells increased on day 3, and Tregs (CD4+CD25+FoxP3+) and Tregs-IL-10 increased at 2 h and 3 d post-IR. The AT2R agonist C21 further increased these phenotypes at all-time points. Th-17 cell accumulation increased at early time points (2 h and 3 d) but returned to normal on day 5 and was not affected by C21 treatment. Ex vivo studies revealed that AT2R agonist promoted CD4+ cell expansion into Tregs, which was blocked by the AT2R antagonist PD123319, PP2A inhibitor okadaic acid, or NO synthase inhibitor L-NAME, suggesting the direct involvement of AT2R-PP2A-NOS pathways.
DISCUSSION: Overall, AT2R activation reduces M1 and promotes Tregs accumulation in IR-AKI, thus shifting the kidney microenvironment towards anti-inflammation and presents a potential mechanism to limit kidney injury and promote repair.
METHODS: Sprague Dawley rats were subjected to 30 min IR without and with AT2R agonist C21 administration. Rats were euthanized at 2 h, 3 d, and 5 d post IR. Flow cytometry of kidney digested cells was performed to analyze kidney infiltrating immune cells. For in-vitro polarization, mouse CD4 T cells were cultured in presence of various stimulus and characterized by flow cytometry and western blot analysis.
RESULTS: On day 3, there was a massive increase in macrophage/monocytes (CD68+) and M1 (CD68+CD86+) cell accumulation and a modest increase in M2 (CD68+CD163+) cell accumulation. The AT2R activation reduced CD68+ and M1 cells accumulation without affecting M2. Accumulation of CD4+CD25+ cells increased on day 3, and Tregs (CD4+CD25+FoxP3+) and Tregs-IL-10 increased at 2 h and 3 d post-IR. The AT2R agonist C21 further increased these phenotypes at all-time points. Th-17 cell accumulation increased at early time points (2 h and 3 d) but returned to normal on day 5 and was not affected by C21 treatment. Ex vivo studies revealed that AT2R agonist promoted CD4+ cell expansion into Tregs, which was blocked by the AT2R antagonist PD123319, PP2A inhibitor okadaic acid, or NO synthase inhibitor L-NAME, suggesting the direct involvement of AT2R-PP2A-NOS pathways.
DISCUSSION: Overall, AT2R activation reduces M1 and promotes Tregs accumulation in IR-AKI, thus shifting the kidney microenvironment towards anti-inflammation and presents a potential mechanism to limit kidney injury and promote repair.