Calcium Uptake via Mitochondrial Uniporter Contributes to Palmitic Acid-Induced Apoptosis in Mouse Podocytes
Calcium Uptake via Mitochondrial Uniporter Contributes to Palmitic Acid-Induced Apoptosis in Mouse Podocytes
复制标题
通过线粒体单向转运蛋白摄取钙有助于棕榈酸诱导小鼠足细胞凋亡
DOI：
10.1002/jcb.25930
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发表时间：
2017-09-01
影响因子：
4
通讯作者：
Peng, Wen
中科院分区：
文献类型：
--
作者：
Yuan, Zeting;Cao, Aili;Peng, Wen
足细胞是肾小球滤过屏障的组成细胞，其凋亡导致的足细胞丢失是导致糖尿病肾病（DN）的蛋白尿的主要原因。因此，深入了解足细胞凋亡机制将有助于更好地了解DN的发病机制，从而有助于制定适当的治疗策略。在这里，我们研究了棕榈酸抑制小鼠足细胞死亡的分子机制，发现棕榈酸以剂量和时间依赖性方式增加细胞死亡。棕榈酸通过上调胞质和线粒体Ca 2+、线粒体膜电位（MMP）、细胞色素c释放和内质网（ER）Ca 2+耗竭诱导足细胞凋亡。细胞内钙螯合剂，1，2-双（2-氨基苯氧基）乙烷-N，N，N，N '-四乙酸四乙酰氧基甲酯（BAPTA-AM）部分阻止了这种上调，而2-氨基乙氧基二苯基硼酸酯（2-APB），一种肌醇1，4，5-三磷酸受体（IP 3R）抑制剂;而阴离子交换抑制剂4，4 '-二异硫氰酸基二苯乙烯-2，2'-二磺酸（DIDS）则没有影响。有趣的是，线粒体Ca 2+单向转运体（MCU）的抑制剂钌红和Ru 360可以阻止棕榈酸诱导的线粒体Ca 2+升高、细胞色素c从线粒体释放到胞质溶胶以及细胞凋亡。针对MCU的siRNA显著减少棕榈酸诱导的细胞凋亡。这些数据表明，通过线粒体单向转运体的Ca 2+摄取有助于棕榈酸诱导的小鼠足细胞凋亡。(c)2017年Wiley Periodicals，Inc.
Podocytes are component cells of the glomerular filtration barrier, and their loss by apoptosis is the main cause of proteinuria that leads to diabetic nephropathy (DN). Therefore, insights into podocyte apoptosis mechanism would allow a better understanding of DN pathogenesis and thus help develop adequate therapeutic strategies. Here, we investigated the molecular mechanism of palmitic acid-inhibited cell death in mouse podocytes, and found that palmitic acid increased cell death in a dose- and time-dependent manner. Palmitic acid induces apoptosis in podocytes through upregulation of cytosolic and mitochondrial Ca2+, mitochondrial membrane potential (MMP), cytochrome c release, and depletion of endoplasmic reticulum (ER) Ca2+. The intracellular calcium chelator, 1,2-bis (2-aminophenoxy) ethane-N,N,N, N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM), partially prevented this upregulation whereas 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-triphosphate receptor (IP3R) inhibitor; dantrolene, a ryanodine receptor (RyR) inhibitor; and 4,4'-diisothiocyanatostibene-2,2'-disulfonic acid (DIDS), an anion exchange inhibitor, had no effect. Interestingly, ruthenium red and Ru360, both inhibitors of the mitochondrial Ca2+ uniporter (MCU), blocked palmitic acid-induced mitochondrial Ca2+ elevation, cytochrome c release from mitochondria to cytosol, and apoptosis. siRNA to MCU markedly reduced palmitic acid-induced apoptosis. These data indicate that Ca2+ uptake via mitochondrial uniporter contributes to palmitic acid-induced apoptosis in mouse podocytes. (c) 2017 Wiley Periodicals, Inc.