Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells.
Mechanism of VEGF expression by high glucose in proximal tubule epithelial cells.
复制标题
DOI：
10.1016/j.mce.2009.09.009
复制
发表时间：
2010-01-15
影响因子：
4.1
通讯作者：
Kasinath, Balakuntalam S.
中科院分区：
文献类型：
--
作者：
Feliers, Denis;Kasinath, Balakuntalam S.
在小鼠近端肾小管上皮细胞中，高糖(HG)作用24小时后，在蛋白和mRNA水平上均可增加血管内皮生长因子的表达，提示其可能是一种转录机制。血管紧张素转换酶抑制剂卡托普利和血管紧张素受体1型受体(AT1)的特异性拮抗剂氯沙坦可阻断血管紧张素转换酶抑制剂卡托普利和血管紧张素1型受体(AT1)特异性拮抗剂氯沙坦的作用，提示血管内皮生长因子的合成是由血管紧张素Ⅱ介导的。血管紧张素原是血管紧张素Ⅱ的前体，血管紧张素原是血管紧张素Ⅱ的前体。虽然肾素和血管紧张素转换酶的表达没有受到影响，但它们的活性都被HG所增强。HG也促进Ang I和Ang II的合成，卡托普利可阻止Ang II的合成增加，但不能阻止Ang I的合成。HG可促进AT1的激活，而卡托普利和氯沙坦可抑制AT1的激活。ERK通路在HG刺激的几分钟内被激活，并持续长达24小时。ERK激活的初始阶段是由HG本身引起的，导致AGT上调，而持续阶段主要是由Ang II激活的AT1受体介导的，导致VEGF合成增加。综上所述，我们的研究表明，MCT表达一种内源性肾素-血管紧张素系统，该系统被HG激活，通过激活ERK途径来刺激VEGF的合成。血管紧张素II(Ang II)和血管内皮生长因子(VEGF)是糖尿病肾损害的重要介质。1型糖尿病小鼠近端肾小管血管内皮生长因子表达增加。小鼠近端肾小管上皮细胞(MCT)在30 mM葡萄糖(HG)培养24 h后，VEGF在蛋白和mRNA水平的表达均增加，提示可能存在转录机制。血管紧张素转换酶抑制剂卡托普利和血管紧张素受体1型受体(AT1)的特异性拮抗剂氯沙坦可阻止血管紧张素转换酶抑制剂卡托普利和血管紧张素受体1型受体(AT1)特异性拮抗剂氯沙坦抑制血管紧张素Ⅱ的合成，提示血管紧张素Ⅱ是由血管紧张素Ⅱ介导的。虽然HG对肾素和ACE的合成没有影响，但在条件培养液中它们的活性增加。HG处理的MCT的条件培养液中Ang I和Ang II的浓度也增加，卡托普利可阻止Ang II的增加，但不能阻止Ang I的合成。最后，在HG处理的MCT中，AT1被激活，其激活被卡托普利和氯沙坦阻止。ERK通路在HG刺激的几分钟内被激活，并持续长达24小时。ERK激活的初始阶段是由HG本身引起的，导致AGT上调，而持续阶段主要是由Ang II激活的AT1受体介导的，导致VEGF合成增加。这些数据表明：1)HG增加AGT的合成和激活MCTs的肾素和ACE，导致局部Ang I和Ang II的产生。2)Ang II激活内源性AT1，刺激血管内皮生长因子的合成。3)ERK的HG激活在几分钟内开始，并持续到24小时。早期ERK的激活参与了AGT的上调，而持续的ERK激活通过AT1参与了血管内皮生长因子的合成。综上所述，我们的研究表明，MCT表达一种内源性肾素-血管紧张素系统，该系统被高糖激活，通过激活ERK途径来刺激血管内皮生长因子的合成。
In mouse proximal tubular epithelial cells, high glucose (HG) for 24 h increases VEGF expression at the protein and the mRNA level, suggesting a transcriptional mechanism. HG-induced VEGF synthesis is prevented by captopril, an inhibitor of angiotensin-converting enzyme, and, by losartan, a specific antagonist of angiotensin type 1 receptor (AT1), suggesting that VEGF synthesis is mediated by Ang II. Synthesis of angiotensinogen (AGT), a precursor of Ang II, is induced by HG. Although renin and ACE expression is not affected, their activity is increased by HG. Ang I and Ang II synthesis is also increased by HG, and captopril prevents increased Ang II, but not Ang I, synthesis. AT1 activation is increased by with HG, and its activation is prevented by captopril and losartan. The ERK pathway is activated by HG within minutes of stimulation and lasting for up to 24h. The initial phase of ERK activation is due to HG itself and leads to AGT upregulation and the sustained phase is mediated for the most part by Ang II-activated AT1 receptor and leads to increased VEGF synthesis. In conclusion, our study shows that MCTs express an endogenous renin-angiotensin system that is activated by HG to stimulate VEGF synthesis, through activation of the ERK pathway. Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. VEGF expression is increased in proximal tubules of mice with type 1 diabetes. In mouse proximal tubular epithelial cells (MCT) cultured with 30 mM glucose (HG) for 24 h, VEGF expression is increased at the protein and the mRNA level, suggesting a transcriptional mechanism. HG stimulation of VEGF synthesis is prevented by captopril, an inhibitor of angiotensin-converting enzyme, and, by losartan, a specific antagonist of angiotensin type 1 receptor (AT1), suggesting that VEGF synthesis is mediated by Ang II. Synthesis of angiotensinogen (AGT), a precursor of angiotensin II, is increased in MCTs cultured in HG. Although synthesis of renin and ACE is not affected by HG, their activity is increased in the conditioned medium. Concentrations of Ang I and Ang II are also increased in conditioned medium from HG-treated MCTs and captopril prevents increased Ang II, but not Ang I, synthesis. Finally, AT1 is activated in MCTs treated with HG, and its activation is prevented by captopril and losartan. The ERK pathway is activated by HG within minutes of stimulation and lasting for up to 24h. The initial phase of ERK activation is due to HG itself and leads to AGT upregulation and the sustained phase is mediated for the most part by Ang II-activated AT1 receptor and leads to increased VEGF synthesis. These data show that: 1) HG increases AGT synthesis and activation of renin and ACE by MCTs, leading to local production of Ang I and Ang II. 2) Ang II activates endogenous AT1 and stimulates synthesis of VEGF. 3) HG activation of ERK starts within minutes and lasts for up to 24h. Early ERK activation is involved in AGT upregulation and sustained ERK activation, mediated via AT1, is responsible for VEGF synthesis. In conclusion, our study shows that MCTs express an endogenous renin-angiotensin system that is activated by high glucose to stimulate the synthesis of VEGF, through activation of the ERK pathway.
登录
查看更多内容
DOI：
10.1152/ajprenal.00271.2004
发表时间：
2005-03-01
影响因子：
4.2
作者：
Feliers, D;Duraisamy, S;Kasinath, BS
通讯作者：
Kasinath, BS
DOI：
10.1083/jcb.107.4.1359
发表时间：
1988-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Haverty TP;Kelly CJ;Hines WH;Amenta PS;Watanabe M;Harper RA;Kefalides NA;Neilson EG
通讯作者：
Neilson EG
影响因子：
15.9
作者：
KAGAMI, S;BORDER, WA;NOBLE, NA
通讯作者：
NOBLE, NA
DOI：
10.1152/ajprenal.00266.2007
发表时间：
2008-04-01
影响因子：
4.2
作者：
Durvasula, Raghu V.;Shankland, Stuart J.
通讯作者：
Shankland, Stuart J.
影响因子：
3
作者：
KRAMER, HJ;GLANZER, K;PREDEL, HG
通讯作者：
PREDEL, HG