Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes.
Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes.
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作者：
Mima A;Hiraoka-Yamomoto J;Li Q;Kitada M;Li C;Geraldes P;Matsumoto M;Mizutani K;Park K;Cahill C;Nishikawa S;Rask-Madsen C;King GL
描述胰高血糖素样肽（GLP）-1信号传导及其对肾内皮功能障碍和肾小球病的影响。我们研究了GLP-1受体（GLP-1 R）在肾小球内皮细胞上的表达和信号传导，以及蛋白激酶A依赖的c-Raf在Ser 259的磷酸化及其对血管紧张素II（Ang II）磷酸化c-Raf（Ser 338）和Erk 1/2磷酸化的抑制。建立内皮细胞蛋白激酶C（PKC）β2过表达小鼠模型（EC-PKCβ 2 Tg）。用GLP-1 R的小干扰RNA分析肾小球内皮细胞中Ang Ⅱ和GLP-1的作用。糖尿病诱导的PKCβ亚型激活通过泛素化增加GLP-1 R的降解和增强磷酸化c-Raf（Ser 338）和Ang II对磷酸化Erk 1/2的激活，从而降低GLP-1 R的表达和对肾内皮的保护作用。EC-PKCβ 2 Tg小鼠表现出GLP-1 R表达降低和磷酸化c-Raf（Ser 338）增加，导致Ang II作用增强。与糖尿病对照组相比，糖尿病EC-PKCβ 2 Tg小鼠表现出内皮GLP-1 R表达和exendin-4保护作用的更大损失，并表现出更多的白蛋白尿和系膜扩张。这些结果表明，GLP-1的肾脏保护作用是通过抑制Ang II对cRaf（Ser 259）的作用介导的，并且由于PKCβ激活和肾小球内皮细胞中GLP-1 R降解增加而被糖尿病削弱。
To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A–dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho–c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho–c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho–c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4–protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.
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影响因子：
2.8
作者：
Tofler, GH;Massaro, J;D'Agostino, RB
通讯作者：
D'Agostino, RB
DOI：
10.1152/ajpheart.00289.2008
发表时间：
2008-07-01
影响因子：
4.8
作者：
Koyanagi, Tomoyoshi;Wong, Lily Y.;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
影响因子：
4.8
作者：
Bullock, BP;Heller, RS;Habener, JF
通讯作者：
Habener, JF
DOI：
10.1053/j.ajkd.2010.06.006
发表时间：
2010-12
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
--
作者：
Goldberg RJ;Nakagawa T;Johnson RJ;Thurman JM
通讯作者：
Thurman JM
影响因子：
7.7
作者：
Naruse, K;Rask-Madsen, C;King, GL
通讯作者：
King, GL