Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers
Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers
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DOI：
10.1152/ajprenal.00293.2010
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发表时间：
2010-10-01
影响因子：
4.2
通讯作者：
Jaimes, Edgar A.
中科院分区：
文献类型：
--
作者：
Hua, Ping;Feng, Wenguang;Jaimes, Edgar A.
Hua P，Feng W，Ji S，Raij L，Jaimes EA.尼古丁增加糖尿病小鼠肾病的严重程度：吸烟者肾脏疾病进展的意义。美国生理学杂志肾脏生理学299：F732-F739，2010年。首次发表于2010年8月4日; doi：10.1152/ajprenal.00293.2010.-流行病学研究已经确定吸烟是慢性肾脏疾病（包括糖尿病肾病）进展的危险因素。我们先前已经报道，尼古丁通过激活非神经元烟碱乙酰胆碱受体促进系膜细胞增殖和肥大，并且尼古丁在急性肾小球肾炎模型中促进肾损伤（Jaimes E，Tian RX，Raij L. Am J Physiol Heart Circ Physiol 292：H76-H82，2007; Jaimes EA，Tian RX，Joshi M，Raij L. Am J Nephrol 29：319-326，2009）。这些研究旨在检验以下假设：尼古丁可减轻db/db小鼠（一种已建立的糖尿病肾病模型）的肾损伤，活性氧作为这些效应的介质发挥重要作用。在这些研究中，将尼古丁（100 μ g/ml）溶于饮用水中给予对照组和db/db小鼠10周。采用尾袖法测量血压，并收集尿液用于蛋白尿。在死亡时，收集肾脏用于组织学和分子生物学。尼古丁给药未导致血压或血糖发生显著变化，并导致可替宁水平与吸烟者血浆中的水平相似。在糖尿病小鼠中，给予尼古丁显著增加尿蛋白排泄（1倍）、肾小球肥大和系膜面积（相似于20%）。这些变化伴随着NADPH氧化酶4的显著增加（类似于30%）以及硝基酪氨酸和Akt表达的增加。在体外，我们确定尼古丁对高糖对人肾小球系膜细胞活性氧生成和Akt磷酸化具有累加效应。这些发现揭示了新的机制，可能会导致新的策略，在治疗和预防糖尿病肾病的吸烟者的发展。
Hua P, Feng W, Ji S, Raij L, Jaimes EA. Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers. Am J Physiol Renal Physiol 299: F732-F739, 2010. First published August 4, 2010; doi:10.1152/ajprenal.00293.2010.-Epidemiological studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of non-neuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, Raij L. Am J Physiol Heart Circ Physiol 292: H76-H82, 2007; Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319-326, 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 mu g/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (similar to 20%). These changes were accompanied by significant increases in NADPH oxidase 4 (similar to 30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers.