4.7 Article

Proximal Tubule Angiotensin AT2 Receptors Mediate an Anti-Inflammatory Response via Interleukin-10 Role in Renoprotection in Obese Rats

期刊

HYPERTENSION
卷 61, 期 6, 页码 1218-+

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.00422

关键词

anti-inflammatory; AT(2) Receptor; C21; interleukin-10; nitric oxide; renoprotection

资金

  1. National Institutes of Health [R01-DK61578]

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The angiotensin type 2 receptor (AT(2)R) has been shown to lower inflammation in the kidney. However, the role of the anti-inflammatory cytokine interleukin (IL)-10 in AT(2)R-mediated attenuation of inflammation has not been elucidated. We hypothesized that AT(2) R activation is renoprotective by directly increasing the levels of anti-inflammatory cytokine IL-10 in the kidney via nitric oxide (NO) signaling. For in vitro studies, the human proximal tubule epithelial cell-line (human kidney-2 [HK-2]) was activated with lipopolysaccharide (10 mu g/mL) and AT(2)R agonist C21 (1 mu mol/L) for 24 hours, and media cytokine levels were assessed. Lipopolysaccharide modestly downregulated AT(2)R expression. Treatment with C21 lowered lipopolysaccharide-induced levels of both tumor necrosis factor-alpha and IL-6, but increased IL-10 levels. Treatment with neutralizing IL-10 antibody (1 mu g/mL) or NO synthase inhibitor L-NAME (1 mmol/L) abolished this effect. For in vivo studies, prehypertensive obese Zucker rats and age-matched lean Zucker rats were treated for 2 weeks with C21 (300 mu g/kg per day, IP) and AT(2)R antagonist (PD123319; 50 mu g/kg per minute, SC infusion). Compared with lean Zucker rats, obese Zucker rats had higher levels of renal AT(2)R expression, tumor necrosis factor-alpha, and IL-6. C21 treatment decreased levels of tumor necrosis factor-alpha by 75% and IL-6 by 60%. Conversely, PD treatment lowered the renal IL-10 levels in obese Zucker rats by approximate to 60%. Renal morphometry revealed increased mesangial matrix expansion and glomerular macrophage infiltration, which was improved by C21 treatment in obese Zucker rats. Our findings suggest that proximal tubule AT(2)R activation is anti-inflammatory by increasing IL10 production, which is largely NO dependent and thus offers renoprotection by preventing early inflammation-induced renal injury in obesity.

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