Glomerular angiotensinogen is induced in mesangial cells in diabetic rats via reactive oxygen species--ERK/JNK pathways.
Glomerular angiotensinogen is induced in mesangial cells in diabetic rats via reactive oxygen species--ERK/JNK pathways.
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DOI：
10.1038/hr.2010.143
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发表时间：
2010-11
影响因子：
5.4
通讯作者：
Kobori, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ohashi, Naro;Urushihara, Maki;Satou, Ryousuke;Kobori, Hiroyuki
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虽然在基础条件下肾内血管紧张素原主要位于近端肾小管细胞中，但先前已有报道在病理条件下血管紧张素原表达在肾小球中被诱导。然而，尚无关于诱导肾小球血管紧张素原的机制的详细信息。我们使用 Zucker 糖尿病肥胖 (ZDF) 肥胖和瘦大鼠的基因对来确定肾小球血管紧张素原的表达。 ZDF肥胖大鼠肾小球血管紧张素原免疫反应水平高于ZDF瘦大鼠。用血管紧张素原和 Thy1.1 抗体进行 IHC 或 IF 双重染色显示，肾小球中的大部分血管紧张素原出现在系膜细胞中。 ZDF 肥胖大鼠的肾小球免疫反应性水平 4-HNE 和 8-异前列腺素（ROS 标志物）尿排泄水平高于 ZDF 瘦大鼠。为了证实这个系统，用过氧化氢（H2O2）处理原代大鼠系膜细胞，以阐明肾小球血管紧张素原表达的信号转导途径。 H2O2 以剂量和时间依赖性方式诱导血管紧张素原表达增加，并且过氧化氢酶抑制 H2O2 诱导的血管紧张素原上调。此外，H2O2 诱导的血管紧张素原上调可被丝裂原激活蛋白激酶 (MAPK) 激酶 (MEK) 抑制剂和 c-Jun N 末端激酶 (JNK) 抑制剂抑制，但不会被 p38 MAPK 抑制剂抑制。这些数据表明，在糖尿病肾病等病理条件下，大部分血管紧张素原是在肾小球系膜细胞中诱导产生的，系膜细胞中血管紧张素原的表达是由H2O2介导的，随后激活细胞外调节激酶（ERK）/JNK通路。
Whereas intra-renal angiotensinogen is predominantly localized in proximal tubular cells under basal conditions, it has been previously reported that angiotensinogen expression is induced in glomeruli under pathological conditions. However, there is no detailed information regarding the mechanism of the induced glomerular angiotensinogen. We used genetic pairs of Zucker diabetic fatty (ZDF) obese and lean rats to determine glomerular angiotensinogen expression. The levels of glomerular angiotensinogen immunoreactivity in ZDF obese rats were higher than those in ZDF lean rats. Double staining by IHC or IF with angiotensinogen and Thy1.1 antibodies showed that the majority of angiotensinogen in glomeruli was seen in mesangial cells. The levels of glomerular immunoreactivity for 4-HNE and urinary excretion of 8-isoprostane—markers of ROS—in ZDF obese rats were higher than those in ZDF lean rats. To confirm this system, primary rat mesangial cells were treated with hydrogen peroxide (H2O2) to clarify the signal transduction pathway for glomerular angiotensinogen expression. H2O2 induced an increase in angiotensinogen expression in a dose- and time-dependent manner, and the H2O2-induced upregulation of angiotensinogen was suppressed by catalase. Furthermore, the H2O2-induced upregulation of angiotensinogen was inhibited by a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor, but not inhibited by a p38 MAPK inhibitor. These data suggest that the majority of angiotensinogen was induced in mesangial cells in glomeruli under pathological conditions such as diabetic nephropathy, and angiotensinogen expression in mesangial cells was mediated by H2O2 and the subsequent activation of extracellular-regulated kinase (ERK)/JNK pathways.
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DOI：
10.1152/ajprenal.00019.2008
发表时间：
2008-09-01
影响因子：
4.2
作者：
Gonzalez-Villalobos, Romer A.;Seth, Dale M.;Navar, L. G.
通讯作者：
Navar, L. G.
影响因子：
19.6
作者：
DARBY, IA;CONGIU, M;COGHLAN, JP
通讯作者：
COGHLAN, JP
影响因子：
13.6
作者：
Kobori, H;Ozawa, Y;Nishiyama, A
通讯作者：
Nishiyama, A
影响因子：
3.6
作者：
DARBY, IA;SERNIA, C
通讯作者：
SERNIA, C
影响因子：
4.1
作者：
Josse, C;Boelaert, JR;Piette, J
通讯作者：
Piette, J