High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression.
High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression.
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DOI：
10.1016/j.cellsig.2015.03.007
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发表时间：
2015-07
影响因子：
4.8
通讯作者：
Choudhury GG
中科院分区：
文献类型：
--
作者：
Dey N;Bera A;Das F;Ghosh-Choudhury N;Kasinath BS;Choudhury GG
高糖环境抑制PTEN表达激活Akt激酶并诱导肾小球系膜细胞肥大及基质蛋白表达高糖抑制PTEN表达的具体机制尚不清楚。我们发现高糖增加了系膜细胞中microRNA-26 a（miR-26 a）的表达。使用具有3 'UTR驱动的荧光素酶的传感器质粒，我们显示PTEN作为miR-26 a响应于高葡萄糖的靶标。miR-26 a的过表达降低了PTEN蛋白水平，导致Akt激酶活性增加，类似于高糖处理。相反，抗miR-26 a逆转了高糖诱导的PTEN抑制，同时抑制了Akt激酶活性。Akt介导的tuberin和PRAS 40磷酸化调节mTORC 1，这是肾小球系膜细胞肥大和基质蛋白表达所必需的。抑制高糖诱导的miR-26 a阻断了tuberin和PRAS 40的磷酸化，这导致抑制了mTORC 1的两种底物S6激酶和4 EBP-1的磷酸化。此外，我们发现miR-26 a的表达诱导肾小球系膜细胞肥大，并增加纤维连接蛋白和胶原I（α2）的表达，类似于高糖孵育的细胞。抗miR-26 a抑制了这些响应于高葡萄糖的现象。我们的研究结果为miR-26 a参与高糖诱导的系膜细胞肥大和基质蛋白表达提供了第一个证据。这些数据表明抗miR-26 a对糖尿病肾病并发症的潜在治疗作用。
High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA-26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3’UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (α2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease.
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影响因子：
4.5
作者：
Grillari, Johannes;Hackl, Matthias;Grillari-Voglauer, Regina
通讯作者：
Grillari-Voglauer, Regina
影响因子：
5.5
作者：
Bera, Amit;Das, Falguni;Choudhury, Goutam Ghosh
通讯作者：
Choudhury, Goutam Ghosh
MicroRNA-26A通过靶向BMP/SMAD1信号来调节病理和生理血管生成。
影响因子：
20.1
作者：
Icli B;Wara AK;Moslehi J;Sun X;Plovie E;Cahill M;Marchini JF;Schissler A;Padera RF;Shi J;Cheng HW;Raghuram S;Arany Z;Liao R;Croce K;MacRae C;Feinberg MW
通讯作者：
Feinberg MW
影响因子：
5.6
作者：
Das, Falguni;Ghosh-Choudhury, Nandini;Bera, Amit;Kasinath, Balakuntalam S.;Choudhury, Goutam Ghosh
通讯作者：
Choudhury, Goutam Ghosh
胰腺癌细胞增殖过程中 miR-26a 介导的细胞周期蛋白 E2 转录后调控的丧失和患者生存率下降
影响因子：
3.7
作者：
Deng J;He M;Chen L;Chen C;Zheng J;Cai Z
通讯作者：
Cai Z