Doxorubicin-Induced Fetal Mesangial Cell Death Occurs Independently of TRPC6 Channel Upregulation but Involves Mitochondrial Generation of Reactive Oxygen Species.
Doxorubicin-Induced Fetal Mesangial Cell Death Occurs Independently of TRPC6 Channel Upregulation but Involves Mitochondrial Generation of Reactive Oxygen Species.
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DOI：
10.3390/ijms22147589
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发表时间：
2021-07-15
影响因子：
5.6
通讯作者：
Adebiyi A
中科院分区：
文献类型：
--
作者：
Matthews AT;Soni H;Robinson-Freeman KE;John TA;Buddington RK;Adebiyi A
多柔比星（DOX）是一种D类妊娠药物，是一种化学治疗剂，在动物研究中已显示可诱导胎儿毒性，包括肾脏异常。瞬时受体电位阳离子（TRPC）6通道的上调参与DOX诱导的足细胞凋亡。我们以前曾报道TRPC6介导的Ca2+信号促进新生肾小球系膜细胞（GMC）死亡。然而，尚不清楚DOX是否改变胎儿系膜TRPC的表达或活力。在本研究中，在对照和DOX处理的来源于胎猪的原代GMC中跟踪细胞生长。活细胞成像显示，暴露于DOX抑制胎猪GMC的增殖并诱导细胞死亡。DOX没有改变TRPC 3的表达水平。相比之下，TRPC 6蛋白在细胞中的表达被DOX显著降低。DOX处理还减弱TRPC 6介导的细胞内Ca 2+升高。DOX刺激GMC产生线粒体活性氧（mtROS）和线粒体自噬。DOX诱导的mtROS产生和凋亡被靶向抗氧化剂mitoquinone逆转。这些数据表明，DOX诱导的胎猪GMC凋亡是独立的TRPC 6通道上调，但需要mtROS的生产。mtROS依赖性GMC死亡可能有助于产前给药时DOX诱导的胎儿肾毒性。
Doxorubicin (DOX), a category D pregnancy drug, is a chemotherapeutic agent that has been shown in animal studies to induce fetal toxicity, including renal abnormalities. Upregulation of the transient receptor potential cation (TRPC) 6 channel is involved in DOX-induced podocyte apoptosis. We have previously reported that TRPC6-mediated Ca2+ signaling promotes neonatal glomerular mesangial cell (GMC) death. However, it is unknown whether DOX alters mesangial TRPC expression or viability in the fetus. In this study, cell growth was tracked in control and DOX-treated primary GMCs derived from fetal pigs. Live-cell imaging demonstrated that exposure to DOX inhibited the proliferation of fetal pig GMCs and induced cell death. DOX did not alter the TRPC3 expression levels. By contrast, TRPC6 protein expression in the cells was markedly reduced by DOX. DOX treatment also attenuated the TRPC6-mediated intracellular Ca2+ elevation. DOX stimulated mitochondrial reactive oxygen species (mtROS) generation and mitophagy by the GMCs. The DOX-induced mtROS generation and apoptosis were reversed by the mitochondria-targeted antioxidant mitoquinone. These data suggest that DOX-induced fetal pig GMC apoptosis is independent of TRPC6 channel upregulation but requires mtROS production. The mtROS-dependent GMC death may contribute to DOX-induced fetal nephrotoxicity when administered prenatally.
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