Nicotine: the link between cigarette smoking and the progression of renal injury?
Nicotine: the link between cigarette smoking and the progression of renal injury?
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DOI：
10.1152/ajpheart.00693.2006
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发表时间：
2007-01-01
影响因子：
4.8
通讯作者：
Raij, Leopoldo
中科院分区：
文献类型：
--
作者：
Jaimes, Edgar A.;Tian, Run-Xia;Raij, Leopoldo
在美国，香烟烟雾（CS）是可预防的发病率和死亡率的最重要来源。最近的临床研究表明，除了是一个主要的心血管危险因素，CS促进肾脏疾病的进展。CS促进慢性肾脏疾病进展的机制尚未阐明。在这里，我们首次证明，人类肾小球系膜细胞（MC）被赋予烟碱乙酰胆碱受体（nAChRs）α 4，α 5，α 7，β 2，β 3和β 4。在其他细胞类型中进行的研究表明，这些nAChR是离子型受体，作为激动剂调节的Ca2+通道发挥作用。尼古丁以剂量依赖性方式诱导MC增殖。在10（-7）M（活跃吸烟者血浆中发现的浓度）时，尼古丁诱导MC增殖[对照组，1，328 +/-50 vs.尼古丁，2，761 +/-90计数/分钟（cpm）; P <0.05]，并增加纤连蛋白的合成（50%），纤连蛋白是参与慢性肾脏疾病进展的关键基质成分。我们和其他人已经表明，响应于PKC激活，MC通过NADPH氧化酶合成活性氧（ROS）。在目前的研究中，我们证明，PKC抑制剂以及diphenyleneiodonium和夹竹桃素，NADPH氧化酶的两种抑制剂，阻止尼古丁对MC增殖和纤连蛋白产生的影响，从而建立活性氧作为尼古丁作用的第二信使。此外，尼古丁增加了ROS的产生，如通过2 '，7'-二氯荧光素二乙酸酯荧光所评估的[对照，184.4 +/-26 vs.尼古丁，281.5 +/-26任意荧光单位（AFU）; n = 5个实验，P <0.05]。这些研究揭示了以前未被认识到的机制，即尼古丁（CS的一种成分）作为一种可能加速和促进肾脏疾病进展的药物。
Cigarette smoke (CS) is the most important source of preventable morbidity and mortality in the United States. Recent clinical studies have suggested that, in addition to being a major cardiovascular risk factor, CS promotes the progression of kidney disease. The mechanisms by which CS promotes the progression of chronic kidney disease have not been elucidated. Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) alpha 4, alpha 5, alpha 7, beta 2, beta 3, and beta 4. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated Ca2+ channels. Nicotine induced MC proliferation in a dose-dependent manner. At 10(-7) M, a concentration found in the plasma of active smokers, nicotine induced MC proliferation [control, 1,328 +/- 50 vs. nicotine, 2,761 +/- 90 counts/minute (cpm); P < 0.05] and increased the synthesis of fibronectin (50%), a critical matrix component involved in the progression of chronic kidney disease. We and others have shown that, in response to PKC activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine on MC proliferation and fibronectin production, hence establishing ROS as second messengers of the actions of nicotine. Furthermore, nicotine increased the production of ROS as assessed by 2', 7'-dichlorofluorescein diacetate fluorescence [control, 184.4 +/- 26 vs. nicotine, 281.5 +/- 26 arbitrary fluorescence units (AFU); n = 5 experiments, P < 0.05]. These studies unveil previously unrecognized mechanisms that indict nicotine, a component of CS, as an agent that may accelerate and promote the progression of kidney disease.