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Anti‐inflammatory Role of Angiotensin AT2 Receptor against LPS‐induced Renal Injury: Role of Interleukin‐10
Author(s) -
Fatima Naureen,
Patel Sanket,
Hussain Tahir
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03037
Subject(s) - agonist , inflammation , medicine , endocrinology , kidney , tumor necrosis factor alpha , cytokine , lipopolysaccharide , renin–angiotensin system , angiotensin ii , receptor antagonist , interleukin , interleukin 6 , receptor , pharmacology , antagonist , blood pressure
Earlier studies in our lab have demonstrated the anti‐inflammatory role of angiotensin‐II type 2 receptor (AT2R) against LPS‐induced inflammation and acute kidney injury (AKI). Interleukin‐10 (IL‐10) is released upon AT2R activation; however, the involvement of IL‐10 in the anti‐inflammatory role of AT2R against LPS‐induced inflammation and AKI is unknown. To address this question, in the present study, male C57BL6/NHsd mice (8‐9 week‐old) were treated with the AT2R agonist C21 (0.3 mg/kg, intraperitoneal, i.p.), LPS (5 mg/kg, i.p.), or LPS with C21 pre‐treatment 1‐hour before LPS, with or without neutralizing IL‐10 antibody (200 μg/mice, i.p.). One set of mice was euthanized 1‐hour after LPS in order to study the alteration in the cytokine profile immediately following these treatments. Since, we did not expect any kidney injury within 1‐hour of LPS treatment, another set of mice was euthanized 24 hours after LPS treatment, and urine samples were collected. Treatment with C21 alone caused an increase in the plasma and kidney IL‐10 levels, which peaks at 2‐hour, and returned to baseline at 6‐hour. The C21‐induced IL‐10 increase was blocked by the AT2R antagonist PD123319 suggesting the role of AT2R. One hour LPS treatment led to high levels of tumor necrosis factor‐α (TNF‐α) and IL‐6 in the plasma and kidney homogenates, and the LPS‐induced increase in these cytokines was attenuated by C21 pre‐treatment (1‐hour prior LPS) both in the plasma and kidney. Neutralizing IL‐10 antibody treatment inhibited the C21‐induced lowering of TNF‐α and IL‐6 in the kidney, but not in the plasma. Furthermore, measurement of the kidney injury markers, i.e. blood urea nitrogen (BUN), and urine creatinine 24 hours post‐LPS treatment revealed that LPS‐induced elevation in BUN and decrease in urine creatinine were effectively mitigated by C21 prior treatment. Neutralizing IL‐10 antibody reversed the effect of C21 by increasing the BUN and decreasing urine creatinine. Collectively, our data suggest that the AT2R‐mediated anti‐inflammation operates in an IL‐10‐dependent manner in organs but an IL‐10‐independent pathway in the blood.