Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway.
Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-α-ROS-p38MAPK pathway.
复制标题
糖尿病肾病浸润巨噬细胞通过TNF-α-ROS-p38MAPK通路促进足细胞凋亡
DOI：
10.18632/oncotarget.18394
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发表时间：
2017-08-08
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Guo Y;Song Z;Zhou M;Yang Y;Zhao Y;Liu B;Zhang X
巨噬细胞浸润与糖尿病肾病（DN）的发病机制有关。然而，浸润巨噬细胞如何影响 DN 的进展尚不清楚。尽管浸润巨噬细胞产生促炎介质并诱导多种靶细胞凋亡，但尚无针对足细胞的研究。因此，我们测试了巨噬细胞对 DN 足细胞凋亡的贡献。体内实验表明，与对照大鼠相比，链脲佐菌素（STZ）诱导的糖尿病大鼠足细胞凋亡增加，并且这种凋亡伴随着肾脏中巨噬细胞浸润的增加。然后，我们建立了共培养系统来研究在不存在或存在高葡萄糖的情况下巨噬细胞和足细胞之间的相互作用。当巨噬细胞在缺乏高葡萄糖的情况下在 Transwell 共培养系统中共培养时，不会引发足细胞凋亡。此外，尽管高糖刺激后足细胞凋亡增加，但与单独在高糖中培养的足细胞相比，在高糖存在下足细胞与巨噬细胞共培养时足细胞凋亡进一步增强。从机制上讲，我们发现巨噬细胞在暴露于高葡萄糖时被激活，表现出促炎性 M1 极化。此外，来自这种高葡萄糖激活的M1巨噬细胞（HG-CM）的条件培养基（CM）以活性氧（ROS）-p38丝裂原激活蛋白激酶（p38MAPK）依赖性方式触发足细胞凋亡，而ROS抑制剂（Tempo）或p38MAPK抑制剂可消除这种凋亡 (SB203580)。最后，我们确定肿瘤坏死因子 (TNF-α) 是高葡萄糖激活巨噬细胞诱导足细胞凋亡的关键介质，因为抗 TNF-α 中和抗体减弱了 HG-CM 诱导的足细胞中的细胞凋亡反应、过量 ROS 生成和 p38MPAK 激活。此外，添加重组TNF-α同样会导致足细胞凋亡。综上所述，高糖激活巨噬细胞释放的TNF-α通过ROS-p38MAPK途径促进足细胞凋亡。阻断高糖激活巨噬细胞分泌 TNF-α 和 ROS-p38MAPK 通路可能是限制足细胞凋亡和延缓糖尿病肾病进展的有效治疗选择。
Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney. Then, we established a co-culture system to study the interaction between macrophages and podocytes in the absence or presence of high glucose. Macrophages did not trigger podocytes apoptosis when they were co-cultured in the absence of high glucose in a transwell co-culture system. Additionally, although podocyte apoptosis was increased after high glucose stimulation, there was a further enhancement of podocyte apoptosis when podocytes were co-cultured with macrophages in the presence of high glucose compared with podocytes cultured alone in high glucose. Mechanistically, we found that macrophages were activated when they were exposed to high glucose, displaying pro-inflammatory M1 polarization. Furthermore, conditioned media (CM) from such high glucose-activated M1 macrophages (HG-CM) trigged podocytes apoptosis in a reactive oxygen species (ROS)-p38mitogen-activated protein kinases (p38MAPK) dependent manner, which was abolished by either a ROS inhibitor (Tempo) or a p38MAPK inhibitor (SB203580). Finally, we identified tumor necrosis factor (TNF-α) as a key mediator of high glucose-activated macrophages to induce podocytes apoptosis because an anti-TNF-α neutralizing antibody blunted the apoptotic response, excess ROS generation and p38MPAK activation in podocytes induced by HG-CM. Moreover, addition of recombinant TNF-α similarly resulted in podocytes apoptosis. In summary, the TNF-α that was released by high glucose-activated macrophages promoted podocytes apoptosis via ROS-p38MAPK pathway. Blockade of TNF-α secretion from high glucose activated macrophages and ROS-p38MAPK pathway might be effective therapeutic options to limit podocytes apoptosis and delay the progression of diabetic nephropathy.
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影响因子：
--
作者：
Yang Z;Xie H;He D;Li L
通讯作者：
Li L
影响因子：
19.6
作者：
Li, J. J.;Kwak, S. J.;Kang, S-W
通讯作者：
Kang, S-W
DOI：
10.1900/rds.2015.12.134
发表时间：
2015-03-01
期刊：
The review of diabetic studies : RDS
影响因子：
--
作者：
Lindblom, Runa;Higgins, Gavin;de Haan, Judy B
通讯作者：
de Haan, Judy B
影响因子：
4.2
作者：
Voloboueva, Ludmila A.;Giffard, Rona G.
通讯作者：
Giffard, Rona G.
影响因子：
19.6
作者：
Chow, F;Ozols, E;Tesch, GH
通讯作者：
Tesch, GH