Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat.
Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat.
复制标题
DOI：
10.1161/circresaha.116.309402
复制
发表时间：
2016-10-28
影响因子：
20.1
通讯作者：
Abboud FM
中科院分区：
文献类型：
--
作者：
Harwani SC;Ratcliff J;Sutterwala FS;Ballas ZK;Meyerholz DK;Chapleau MW;Abboud FM
肾脏炎症参与了高血压的病理生理过程。CD161a+免疫细胞在自发性高血压大鼠(SHR)中占主导地位，并在烟碱能胆碱能激活时扩张。我们旨在研究尼古丁激活胆碱能后高血压前期SHR中CD161a+免疫细胞的表型，并确定这些细胞是否参与了肾脏炎症和高血压的发展。研究使用了年轻的SHR和Wistar京都(WKY)大鼠。脾细胞和骨髓细胞体外暴露于尼古丁，体内注入尼古丁。测量血压、肾脏、血清和尿液。采用流式细胞术、Luminex/ELISA法、免疫组织化学、共聚焦显微镜和Western印迹等方法。烟碱胆碱能激活可诱导SHR来源的脾细胞中CD161a+/CD68+巨噬细胞的增殖、肾脏浸润和早产性高血压。这些变化与肾脏单核细胞趋化蛋白-1(MCP-1)和极晚期抗原-4(VLA-4)的表达增加有关。CD161a的配体凝集素样转录本1(LLT1)在SHR肾脏中高表达，而血管细胞黏附分子(VCAM-1)和细胞间黏附分子(ICAM-1)与WKY相似。注射尼古丁后，自发性高血压大鼠肾脏和尿中炎性细胞因子升高。失神经肾组织中尼古丁介导的巨噬细胞浸润/炎症反应增强，这不能用血管紧张素II水平或血管紧张素1/2受体的表达来解释。此外，抗炎的α-7-烟碱-乙酰胆碱受体在青年自发性高血压大鼠和成年大鼠中的表达相似。在年轻的自发性高血压患者中存在一种新的、遗传的尼古丁胆碱能炎症效应，通过CD161a+/CD68+巨噬细胞的扩张来测量。这会导致肾脏炎症和早产儿高血压，部分原因可能是肾脏LLT-1、MCP-1和VLA-4的表达增加。
Renal inflammation contributes to the pathophysiology of hypertension. CD161a+ immune cells are dominant in the Spontaneously Hypertensive Rat (SHR) and expand in response to nicotinic cholinergic activation. We aimed to phenotype CD161a+ immune cells in pre-hypertensive SHR following cholinergic activation with nicotine, and determine if these cells are involved in renal inflammation and the development of hypertension. Studies utilized young SHR and Wistar Kyoto (WKY) rats. Splenocytes and bone marrow cells were exposed to nicotine ex-vivo and nicotine was infused in-vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a+/CD68+ macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of monocyte-chemoattractant-protein-1 (MCP-1) and very-late-antigen-4 (VLA-4). Lectin-Like-Transcript 1 (LLT1), the ligand for CD161a, was overexpressed in SHR kidney, while vascular cellular (VCAM-1) and intracellular adhesion molecules (ICAM-1) were similar to WKY. Inflammatory cytokines were elevated in SHR kidney and urine following nicotine infusion. Nicotine mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin-II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nicotinic-acetylcholine receptor was similar in young SHR and WKY. A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a+/CD68+ macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.