Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats.
Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats.
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DOI：
10.1161/hypertensionaha.111.00422
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Hussain T
中科院分区：
文献类型：
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作者：
Dhande I;Ali Q;Hussain T
血管紧张素AT 2受体（AT 2 R）已被证明可以降低肾脏中的炎症。然而，抗炎细胞因子IL-10在AT 2 R介导的炎症减轻中的作用尚未阐明。我们假设AT 2 R激活通过一氧化氮（NO）信号直接增加肾脏中抗炎细胞因子IL-10的水平来保护肾脏。对于体外研究，用脂多糖（LPS，10 μg/ml）和/或AT 2 R激动剂C21（1μmol/L）活化人近端小管上皮细胞系（HK-2）24小时，并评估培养基细胞因子水平。LPS适度下调AT 2 R表达。C21处理降低LPS诱导的TNF-α和IL-6水平，但增加IL-10水平。用中和性IL-10抗体（1 μg/ml）或NO合成酶抑制剂L-NAME（1 mmol/L）处理可阻断这种作用。对于体内研究，用C21（300 μg/kg/天，i.p）和/或AT 2 R拮抗剂（PD 123319，50 μg/kg/min，s.c.输注）。与LZR相比，OZR具有较高水平的肾AT 2 R表达、TNF-α和IL-6。C21治疗使TNF-α水平降低75%，IL-6水平降低60%。相反，PD治疗使OZR患者的肾脏IL-10水平降低约60%。肾形态计量学显示增加的系膜基质扩张和肾小球巨噬细胞浸润，在OZR中通过C21治疗得到改善。我们的研究结果表明，近端小管AT 2 R的激活是通过增加IL-10的产生，这在很大程度上是NO依赖性的抗炎，从而提供肾脏保护，防止早期炎症诱导的肾损伤肥胖。
The angiotensin AT2 receptor (AT2R) has been shown to lower inflammation in the kidney. However the role of the anti-inflammatory cytokine IL-10 in AT2R mediated attenuation of inflammation has not been elucidated. We hypothesized that AT2R 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 (HK-2) was activated with lipopolysaccharide (LPS, 10 μg/ml) and/or AT2R agonist C21 (1μmol/L) for 24 hours and media cytokine levels were assessed. LPS modestly downregulated AT2R expression. Treatment with C21 lowered LPS-induced levels of both, TNF-α and IL-6 but increased IL-10 levels. Treatment with neutralizing IL-10 antibody (1 μg/ml) or NO synthase inhibitor L-NAME (1 mmol/L) abolished this effect. For in vivo studies, pre-hypertensive obese Zucker rats (OZR) and age-matched lean Zucker rats were treated for 2 weeks with C21 (300 μg/kg/day, i.p) and/or AT2R antagonist (PD123319, 50 μg/kg/min, s.c. infusion). Compared to LZR, OZR had higher levels of renal AT2R expression, TNF-α and IL-6. C21 treatment decreased levels of TNF-α by 75% and IL-6 by 60%. Conversely, PD treatment lowered the renal IL-10 levels in OZR by ~60%. Renal morphometry revealed increased mesangial matrix expansion and glomerular macrophage infiltration which was improved by C21 treatment in OZR. Our findings suggest that proximal tubule AT2R activation is anti-inflammatory by increasing IL-10 production which is largely NO-dependent and thus offers renoprotection by preventing early inflammation-induced renal injury in obesity.