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首页> 外文期刊>BMC Nephrology >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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IP 3 R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model

机译：IP 3 R-GRP75-VDAC1-MCU钙调节轴拮抗剂免受凋亡和蛋白尿中的蛋白肾病大鼠模型中的蛋白尿中的诱饵

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摘要

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.
机译：阴细胞凋亡的机制尚不完全理解。此外，肌醇1,4,5-三磷酸受体（IP3R）/葡萄糖调节蛋白质75（GRP75）/电压依赖性阴离子通道1（VDAC1）/线粒体钙的单钙（MCU）钙调节轴（MCU）的作用位于内质网（ER）线粒体偶联的偶联，在足细胞凋亡的机制中尚不清楚。本研究旨在了解该轴在足细胞凋亡中的作用，探讨促进足细胞保护的潜在靶标。在培养的小鼠泛囊细胞中，分析了IP3R，GRP75，VDAC1和MCU和线粒体CA2 +的表达和线粒体CA2 +。使用共免疫沉淀实验研究了IP3R，GRP75和VDAC1之间的相互作用。 IP3R，GRP75和MCU激动剂和拮抗剂对培养的诱导诱导的诱导诱导诱导型诱导的诱导型诱导型多粒细胞效应对线粒体CA2 +和细胞凋亡的影响。在具有亚霉素诱导的肾病的大鼠中进一步研究了MCU抑制剂的泛细胞保护作用。在Adriamycin-或血管紧张素II诱导的小鼠泛细胞凋亡期间，确认了IP3R-GRP75-VDAC1复合物中IP3R-GRP75-VDAC1复合物，线粒体CA2 +过载和增加的活性CASPase-3水平的增强的相互作用。该轴的激动剂促进了线粒体CA2 +过载和泛孔细胞凋亡，而针对IP3R，GRP75或MCU的特异性拮抗剂防止了线粒体CA2 +过载和泛细胞凋亡。特定的MCU抑制剂防止了大鼠的亚霉素诱导的蛋白尿和足细胞足部工艺患者。该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 +过载而介导的泛细胞凋亡。抑制来自ER的CA2 +转移到线粒体的拮抗剂免受细胞凋亡的影响。 MCU抑制剂在具有亚霉素诱导的肾病的大鼠中受到保护的多粒细胞和降低的蛋白尿。因此，对该途径的拮抗剂承诺作为新型泛细胞保护药物。

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