mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis
mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis
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mPGES-1衍生的前列腺素E2刺激Stat3促进足细胞凋亡
DOI：
10.1007/s10495-017-1418-7
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发表时间：
2017-11-01
期刊：
影响因子：
7.2
通讯作者：
Jia, Zhanjun
中科院分区：
文献类型：
--
作者：
Yu, Jing;Wu, Yimei;Jia, Zhanjun
我们以前报道，微粒体前列腺素E合成酶-1（mPGES-1）有助于阿霉素（Adr）诱导足细胞凋亡。然而，其分子机制仍不清楚。我们研究了mPGES-1/PGE 2级联在激活Stat 3信号中的作用以及Stat 3在PGE 2和Adr诱导的足细胞凋亡中的作用。在小鼠足细胞中，PGE 2剂量和时间依赖性地增加Stat 3的磷酸化，与增强的细胞凋亡和减少的足细胞蛋白podocin一致。与增加的Stat 3磷酸化一致，Stat 3衍生的细胞因子包括IL-6、IL-17、MCP-1和ICAM-1在PGE 2处理后显著上调。通过应用特定的Stat 3抑制剂S3 I-201，PGE 2诱导的足细胞凋亡在很大程度上被取消与podocin减少的阻断平行。接下来，我们观察到Adr处理也增强了p-Stat 3并激活了mPGES-1/PGE 2级联。S3 I-201阻断Stat 3可显著改善Adr诱导的细胞凋亡和podocin减少。更有趣的是，通过mPGES-1 siRNA沉默足细胞中的mPGES-1阻断了Adr诱导的Stat 3磷酸化、PGE 2产生和Stat 3衍生的炎性细胞因子的增加。综上所述，本研究表明mPGES-1衍生的PGE 2可以激活Stat 3信号，促进足细胞凋亡。靶向mPGES-1/PGE 2/Stat 3信号通路可能是治疗足细胞病的潜在策略。
We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time-dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy.