IP(3)R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.
IP(3)R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.
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IP3R-Grp75-VDAC1-MCU 钙调节轴拮抗剂可保护阿霉素肾病大鼠模型中的足细胞免于凋亡并减少蛋白尿
DOI：
10.1186/s12882-018-0940-3
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发表时间：
2018-06-15
期刊：
影响因子：
2.3
通讯作者：
Zhu SN
中科院分区：
文献类型：
--
作者：
Xu H;Guan N;Ren YL;Wei QJ;Tao YH;Yang GS;Liu XY;Bu DF;Zhang Y;Zhu SN
足细胞凋亡的机制尚未完全清楚。此外，位于内质网（ER）-线粒体偶联位点的1，4，5-三磷酸肌醇受体（IP3R）/葡萄糖调节蛋白75（Grp75）/电压依赖性阴离子通道1（VDAC 1）/线粒体钙单向转运体（MCU）钙调节轴在足细胞凋亡机制中的作用尚不清楚。本研究旨在了解该轴在足细胞凋亡中的作用，并探索足细胞保护的潜在靶点。在阿霉素或血管紧张素II诱导的小鼠足细胞凋亡过程中，分析了IP3R、Grp75、VDAC 1和MCU的表达以及线粒体Ca2+。使用免疫共沉淀实验研究了IP3R、Grp75和VDAC 1之间的相互作用。在培养的足细胞中研究了IP3R、Grp75和MCU激动剂和拮抗剂对线粒体Ca2+和凋亡的影响。在阿霉素诱导的肾病大鼠中进一步研究了MCU抑制剂的足细胞保护作用。在阿霉素或血管紧张素II诱导的小鼠足细胞凋亡过程中，IP3R、Grp75、VDAC 1和MCU的表达增加，IP3R-Grp75-VDAC 1复合物之间的相互作用增强，线粒体Ca2+超载，以及活性caspase-3水平增加均得到证实。该轴的激动剂促进线粒体Ca2+超载和足细胞凋亡，而针对IP3R，Grp75或MCU的特异性拮抗剂防止线粒体Ca2+超载和足细胞凋亡。一种特异性MCU抑制剂可预防阿霉素诱导的蛋白尿和大鼠足细胞足突消失。本研究确定了一种新的途径，其中IP3R-Grp75-VDAC1-MCU钙调节轴通过促进线粒体Ca2+过载介导足细胞凋亡。拮抗剂，抑制钙离子从ER转移到线粒体保护小鼠足细胞凋亡。一种MCU抑制剂保护阿霉素肾病大鼠足细胞并减少蛋白尿因此，该途径的拮抗剂有望成为新型足细胞保护药物。
The mechanism of podocyte apoptosis is not fully understood. In addition, the role of the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (Grp75)/voltage-dependent anion channel 1 (VDAC1)/mitochondrial calcium uniporter (MCU) calcium regulation axis, which is located at sites of endoplasmic reticulum (ER) mitochondria coupling, in the mechanism of podocyte apoptosis is unclear. This study aimed to understand the roles of this axis in podocyte apoptosis and explore potential targets for podocyte protection. The expression of IP3R, Grp75, VDAC1, and MCU and mitochondrial Ca2+ were analyzed during Adriamycin- or angiotensin II-induced apoptosis in cultured mouse podocytes. The interaction between IP3R, Grp75, and VDAC1 was investigated using co-immunoprecipitation experiments. The effects of IP3R, Grp75, and MCU agonists and antagonists on mitochondrial Ca2+ and apoptosis were investigated in cultured podocytes. The podocyte-protective effects of an MCU inhibitor were further investigated in rats with Adriamycin-induced nephropathy. Increased expression of IP3R, Grp75, VDAC1 and MCU, enhanced interaction among the IP3R-Grp75-VDAC1 complex, mitochondrial Ca2+ overload, and increased active caspase-3 levels were confirmed during Adriamycin- or angiotensin II-induced mouse podocyte apoptosis. Agonists of this axis facilitated mitochondrial Ca2+ overload and podocyte apoptosis, whereas specific antagonists against IP3R, Grp75, or MCU prevented mitochondrial Ca2+ overload and podocyte apoptosis. A specific MCU inhibitor prevented Adriamycin-induced proteinuria and podocyte foot process effacement in rats. This study identified a novel pathway in which the IP3R-Grp75-VDAC1-MCU calcium regulation axis mediated podocyte apoptosis by facilitating mitochondrial Ca2+ overload. Antagonists that inhibit Ca2+ transfer from ER to mitochondria protected mouse podocytes from apoptosis. An MCU inhibitor protected podocytes and decreased proteinuria in rats with Adriamycin-induced nephropathy. Therefore, antagonists to this pathway have promise as novel podocyte-protective drugs.
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DOI：
10.1007/s00467-015-3224-1
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期刊：
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