Metadherin facilitates podocyte apoptosis in diabetic nephropathy.
Metadherin facilitates podocyte apoptosis in diabetic nephropathy.
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元通蛋白促进糖尿病性肾病中的足细胞凋亡。
DOI：
10.1038/cddis.2016.335
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发表时间：
2016-11-24
影响因子：
9
通讯作者：
Long HB
中科院分区：
文献类型：
--
作者：
Liu WT;Peng FF;Li HY;Chen XW;Gong WQ;Chen WJ;Chen YH;Li PL;Li ST;Xu ZZ;Long HB
细胞凋亡是足细胞丢失的主要原因之一，据报道在糖尿病肾病（DN）发病机制中起着至关重要的作用，了解足细胞凋亡调节的机制至关重要。 Metadherin (MTDH) 是一种重要的癌基因，在大多数癌症中过度表达，导致细胞凋亡、转移和患者生存率低。在这里，我们发现，在 DN 大鼠模型的肾小球和高糖 (HG) 诱导的条件永生化小鼠足细胞 (MPC5) 中，Mtdh 和磷酸化 p38 丝裂原激活蛋白激酶 (MAPK) 的表达水平显着增加，而 microRNA-30 家族成员 (miR-30s) 的表达水平显着降低。这些水平与足细胞凋亡率呈正相关。使用小干扰 RNA 而非 Mtdh 过表达来抑制 Mtdh 表达，可抑制 HG 诱导的 MPC5 细胞凋亡和 p38 MAPK 通路以及 Bax 和 cleaved caspase 3 表达。这与 p38 MAPK 抑制剂 (SB203580) 的作用相似。此外，荧光素酶测定结果表明，Mtdh 代表 miR-30 的靶标。使用miR-30 microRNA (miRNA)抑制剂的瞬时转染实验导致Mtdh表达增加并诱导MPC5细胞凋亡，而与各自的对照相比，用miR-30 miRNA模拟物处理导致HG诱导的MPC5细胞Mtdh表达和细胞凋亡减少。我们的结果表明，Mtdh 是足细胞凋亡的有效调节剂，并且它代表 miR-30 miRNA 的靶标，通过激活 HG 诱导的 p38 MAPK 依赖性途径促进足细胞凋亡。
Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.