Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission.
Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission.
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DOI：
10.1038/s41419-020-03022-7
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发表时间：
2020-09-29
影响因子：
9
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Deng Q;Wen R;Liu S;Chen X;Song S;Li X;Su Z;Wang C
过度的线粒体裂变在糖尿病肾病（DKD）的足细胞损伤中起关键作用，而长链非编码RNA（lncRNA）在DKD的发生发展过程中也至关重要。然而，目前对于lncRNA对足细胞线粒体裂变的调控机制知之甚少。在此，我们利用人足细胞以及Meg3足细胞特异性敲低小鼠，在体内和体外研究了长链非编码RNA母系表达基因3（Meg3）在线粒体裂变中的作用。在链脲佐菌素（STZ）诱导的糖尿病小鼠中，lncRNA Meg3的表达升高，且与足细胞数量相关。在足细胞特异性Meg3敲低的糖尿病小鼠中，足细胞过度的线粒体裂变以及肾脏组织病理和生理参数均得到改善。在Meg3敲除的足细胞中，线粒体伸长，足细胞损伤减轻，同时动力相关蛋白1（Drp1）向线粒体的转位减少。相比之下，在过表达lncRNA Meg3的足细胞中，观察到线粒体碎片化增加、足细胞损伤加重以及Drp1表达和磷酸化增强。用线粒体分裂抑制剂1（Mdivi1）处理过表达lncRNA Meg3的足细胞后，线粒体过度碎片化明显减弱，足细胞损伤减轻。最后，经Mdivi1处理后，高糖诱导的线粒体碎片化和Drp1向线粒体的转位均减少。我们的数据表明，Meg3在人源细胞和糖尿病小鼠的足细胞中表达均升高，其通过增加Drp1及其向线粒体的转位来调节线粒体裂变，进而导致足细胞损伤。
Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.
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DOI：
10.1083/jcb.201511036
发表时间：
2016-02-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mishra P;Chan DC
通讯作者：
Chan DC
影响因子：
6.6
作者：
Bai, Xiaoyan;Geng, Jian;Liu, Xiaoting
通讯作者：
Liu, Xiaoting
影响因子：
13.6
作者：
Ayanga, Bernard A.;Badal, Shawn S.;Danesh, Farhad R.
通讯作者：
Danesh, Farhad R.
影响因子：
13.6
作者：
Wharram, BL;Goyal, M;Wiggins, RC
通讯作者：
Wiggins, RC
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C