Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia:: Role in leptin-induced hypertension
Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia:: Role in leptin-induced hypertension
复制标题
DOI：
10.1016/j.bcp.2008.01.003
复制
发表时间：
2008-04-15
影响因子：
5.8
通讯作者：
Beltowski, Jerzy
中科院分区：
文献类型：
--
作者：
Jamroz-Wisniewska, Anna;Wojcicka, Grazyna;Beltowski, Jerzy
我们研究了表皮生长因子（EGF）受体在瘦素诱导的大鼠高血压发病机制中的作用。瘦素以递增剂量（0.1-0.5 mg/kg/天）连续10天给药，主动脉和肾脏中非受体酪氨酸激酶、c-Src、EGF受体和细胞外信号调节激酶（ERK）的磷酸化水平增加，同时异前列腺素和H2O2的血浆浓度和尿排泄增加。接受瘦素治疗的动物的血压和肾Na+,K+-ATP酶活性较高，而尿钠排泄较低。 NADPH氧化酶抑制剂罗布麻宁、Src激酶抑制剂PP2、EGF受体抑制剂AG1478、蛋白法尼基转移酶抑制剂手霉素A和ERK抑制剂PD98059消除了瘦素对肾Na+、K+-ATP酶、尿钠排泄和血压的影响。相比之下，胰岛素样生长因子-1 和血小板衍生生长因子受体的抑制剂 AG1024 和 AG1295 分别仅轻微降低 ERK 磷酸化，并且对接受瘦素的大鼠的血压没有影响。这些数据表明：（1）实验性高瘦素血症。与氧化应激和 EGF 受体的 c-Src 依赖性反式激活有关，刺激血管壁和肾脏中的 ERK，(2) EGF 受体-ERK 通路过度活跃，通过刺激肾 Na+、K+-ATP 酶和减少钠排泄，导致瘦素诱导的高血压。(3) c-Src、EGF 受体和 ERK 的抑制剂可被视为治疗与高瘦素血症相关的高血压的新疗法，例如瘦素血症。肥胖和代谢综合征患者。 (c) 2008 Elsevier Inc. 保留所有权利。
We examined the role of epidermal growth factor (EGF) receptor in the pathogenesis of leptin-induced hypertension in the rat. Leptin, administered in increasing doses (0.1-0.5 mg/kg/day) for 10 days, increased phosphorylation levels of non-receptor tyrosine kinase, c-Src, EGF receptor and extracellular signal-regulated kinases (ERK) in aorta and kidney, which was accompanied by the increase in plasma concentration and urinary excretion of isoprostanes and H2O2. Blood pressure and renal Na+,K+-ATPase activity were higher, whereas urinary sodium excretion was lower in animals receiving leptin. The effects of leptin on renal Na+,K+-ATPase, natriuresis and blood pressure were abolished by NADPH oxidase inhibitor, apocynin, Src kinase inhibitor, PP2, EGF receptor inhibitor, AG1478, protein farnesyltransferase inhibitor, manumycin A, and ERK inhibitor, PD98059. In contrast, inhibitors of insulin-like growth factor-1 and platelet-derived growth factor receptors, AG1024 and AG1295, respectively, only slightly reduced ERK phosphorylation and had no effect on blood pressure in rats receiving leptin. These data indicate that: (1) experimental hyperleptinemia. is associated with oxidative stress and c-Src-dependent transactivation of the EGF receptor, which stimulates ERK in vascular wall and the kidney, (2) overactivity of EGF receptor-ERK pathway contributes to leptin-induced hypertension by stimulating renal Na+,K+-ATPase and reducing sodium excretion, (3) inhibitors of c-Src, EGF receptor and ERK may be considered as a novel therapy for hypertension associated with hyperleptinemia, e.g. in patients with obesity and metabolic syndrome. (c) 2008 Elsevier Inc. All rights reserved.