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

Ali, Riyasat; Patel, Sanket; Hussain, Tahir

doi:10.1152/ajprenal.00507.2020

Cited by 19 publications

(14 citation statements)

References 62 publications

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“…Additionally, resident macrophages are also present in the kidney (Munro and Hughes, 2017). Our work and previous literature has suggested the involvement of proximal tubular epithelial cells (Dhande et al, 2013), macrophages (Dhande et al, 2015), T-cells (Curato et al, 2010;Skorska et al, 2015), dendritic cells (Ma et al, 2019) and Treg cells (Ali et al, 2021) as a source of IL-10 upon AT2R stimulation. This could be responsible for higher concentrations of renal IL-10 as compared to plasma.…”

Section: Discussionsupporting

confidence: 71%

“…Therefore, another set of animals were treated with the same regimen and euthanized 24 h after LPS treatment (Protocol 4). Renal functional indices BUN and creatinine, and tubular injury are early diagnostic markers for AKI (Basile et al, 2012;Fattah and Vallon, 2018) and the protective role of AT2R against IR-induced AKI has been demonstrated in another study in our laboratory (Ali et al, 2021). In view of the findings from our laboratory in I/R and LPS models of AKI, the levels of BUN and urinary creatinine were again measured in the 24-h samples.…”

Section: Discussionmentioning

confidence: 83%

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Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

2021

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Acute kidney injury (AKI) due to endotoxemic insult is predicted by the infiltration of neutrophils, monocytes and macrophages, and the release of pro-and anti-inflammatory cytokines to the site of injury. Earlier, we have demonstrated the role of angiotensin-II type 2 receptor (AT2R) stimulation in reno-protection in lipopolysaccharide (LPS)-induced inflammation and AKI in C57BL6/NHsd mice. Moreover, AT2R activation has been shown to increase the anti-inflammatory cytokine interleukin-10 (IL-10), its role in AT2R-mediated anti-inflammation and reno-protection is unknown. To address this question, in the present study mice were treated with the AT2R agonist C21 (0.3 mg/kg, intraperitoneally), LPS (5 mg/kg, intraperitoneally), or LPS with C21 pre-treatment with or without neutralizing IL-10 antibody. Treatment with C21 alone caused an increase in the plasma and kidney IL-10 levels, which peaks at 2-h, and returned to baseline at 6-h. The C21-induced IL-10 increase was blocked by the AT2R antagonist PD123319 suggesting AT2R’s involvement. LPS treatment caused a profound increase in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the LPS-induced increase in these cytokines was attenuated by the C21 pre-treatment (1-h prior LPS) both in the plasma and kidney. Neutralizing IL-10 antibody treatment abrogated the C21-lowering of TNF-α and IL-6 in the kidney but not in the plasma. Similar results as related to the cytokines profiles in all the groups were also observed in the heart and spleen. The alteration in early cytokine profile prompted us to measure the markers of renal function (blood urea nitogen and urinary creatinine) in order to analyze the effect of IL-10 neutralization. However, it was too early to observe changes in renal function. Therefore, the renal function and injury markers were again measured at 24 h. Treatment with neutralizing IL-10 antibody attenuated the C21-mediated improvement in indices of the kidney function, but not the biomarkers of renal injury (kidney injury molecule-1 and neutrophil-gelatinase associated lipocalin). Collectively, our data suggest that the involvement of IL-10 in AT2R-mediated anti-inflammation and reno-protection against LPS is complex, mediating the renal cytokine profile and kidney filtration function, but not the plasma cytokine profile and renal injury markers.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 83%

Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

2021

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“…Renin-angiotensin system is an important hormonal system involved in regulating renal structure and function, of which abnormal activation triggers the deleterious effects of angiotensin II [ 29 ]. As a component of the renin-angiotensin system, angiotensin type 2 (AT 2) receptor (AT2R) is believed to be renoprotective by functionally antagonizing the proinflammatory actions of angiotensin II, rendering to protecting organs from injury, including AKI [ 30 , 31 ]. Given the close relationship between AT2R and IL-10 has been reported in various research on renal diseases, we wonder whether the renoprotective function of IL-10 is associated with AT2R.…”

Section: Discussionmentioning

confidence: 99%

Double-Negative T Cells Attenuate Cisplatin-Induced Acute Kidney Injury via Upregulating IL-10/AT2R Axis

Gong

Zhang

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. Our previous research showed that TCR+CD4-CD8-double-negative (DN) T cells protect renal epithelial cells from cisplatin-induced acute kidney injury (AKI). Therefore, this study is aimed at investigating the mechanism underlying the effect of DN T cells against Cis-induced AKI. Methods. HK-2 cells cultured alone or with DN T cells were treated with or without Cis. After treatment, the cell viability and death were analyzed by a CCK-8 kit and flow cytometric assay with Annexin V/PI staining, respectively. The expressions of inflammatory factors in HK-2 and DN T cells were analyzed using qPCR. The expression levels of nephrotoxicity-associated biomarkers (KIM, calbindin, and TIMP-1), Bcl-2, and angiotensin AT2 receptor (AT2R) were determined by Western blot and qPCR. Results. The administration of cisplatin significantly decreased the cell viability and AT2R expression, and increased cell death, inflammatory factors, and nephrotoxicity-associated biomarkers of HK-2 cells, while these effects were partly attenuated when cocultured with DN T cells. IL-10 expression was significantly increased in DN T cells after coculture, and cisplatin treatment aggravated this elevation. IL-10 supplementation exhibited a similar effect to coculture, whereas anti-IL-10 antibody reversed the effect of coculture on cisplatin-treated HK-2 cells. Finally, PD123319, an AT2R antagonist, also reversed the effect of IL-10 and coculture on the cell viability, death, and the expression of KIM, calbindin, TIMP-1, and Bcl-2 of cisplatin-treated HK-2 cells. Conclusions. DN T cells protected HK-2 cells from cisplatin-induced injury through IL-10/AT2R axis, which may act as a potential target for the treatment of cisplatin-induced AKI.

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“…We found that C21 raises the numbers of CD4 + CD25 + FoxP3 + T cells in CIA, a fact that likely contributed to the improvement of arthritis. Recently, Hussain et al showed protective effects of C21 on kidney ischemia by modulation of CD4 T cells towards the regulatory T cell phenotype (79).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers

et al. 2022

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The angiotensin AT2 receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT2R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT2R-stimulation with the selective non-peptide AT2R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4+CD25+FoxP3+ regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4+FoxP3+ cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4+IL-17A+ and CD4+IFN-gamma+ T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT2R-stimulation promotes the expansion of CD4+ regulatory T cells and suppresses IL-17A production. Thus, AT2R-stimulation may represent an attractive treatment strategy for arthritis.

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

Cited by 19 publications

References 62 publications

Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

Double-Negative T Cells Attenuate Cisplatin-Induced Acute Kidney Injury via Upregulating IL-10/AT2R Axis

Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers

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