Necroptosis in 3-chloro-1, 2-propanediol (3-MCPD)-dipalmitate-induced acute kidney injury in vivo and its repression by miR-223-3p
Necroptosis in 3-chloro-1, 2-propanediol (3-MCPD)-dipalmitate-induced acute kidney injury in vivo and its repression by miR-223-3p
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DOI：
10.1016/j.tox.2018.05.015
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发表时间：
2018-08-01
期刊：
影响因子：
4.5
通讯作者：
Yu, Liangli (Lucy)
中科院分区：
文献类型：
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作者：
Huang, Guoren;Xue, Jinli;Yu, Liangli (Lucy)
3-氯-1，2-丙二醇酯(3-MCPD)是一类加工过程中产生的具有肾毒性的食品污染物。本研究探讨了坏死性下垂在3-MCPD-二棕榈酸酯(2.5g/kgbw)对C57BL/6小鼠的肾毒性作用中是否起作用以及如何起作用。结果表明，在3-MCPD-二棕榈酸酯诱导的急性肾损伤(AKI)中，坏死下垂途径中的主要成分受体相互作用蛋白1(RIPK1)、RIPK3和混合谱系蛋白样蛋白(MLKL)表达上调。RIPK3或MLKL的缺失和RIPK1的抑制抑制了AKI。在RIPK3或MLKL缺陷的小鼠中，3-MCPD-二棕榈酸酯处理的小鼠肾脏中炎性细胞因子的上调被减弱，这表明一个涉及坏死下垂和炎症的正反馈回路。MicroRNA分析表明，38个已知的miRNAs和40个新的miRNAs在3-MCPD-二棕榈酸酯处理的肾脏中差异表达(DE)。在这些miRNAs中，miR-223-3p在3-MCPD-二棕榈酸酯诱导的AKI过程中显著上调。在培养的小鼠近端肾小管上皮细胞中，miR-223-3p模拟物可抑制RIPK3的表达，该作用可被miR-223-3p抑制剂阻断。荧光素酶报告实验证实miR-223-3p通过靶向RIPK3的3‘非翻译区而抑制RIPK3的表达。这些结果提示，坏死性下垂与3-MCPD-二棕榈酸酯所致的急性肾损伤有关，miR-223-3p可减轻这种损伤。
Fatty acid esters of 3-chloro-1, 2-propanediol (3-MCPD) are a group of processing-induced food contaminants with nephrotoxicity. This study investigated whether and how necroptosis played a role in the nephrotoxic effect of 3-MCPD-dipalmitate (2.5 g/kg BW) in C57 BL/6 mice. The results showed that the principal components in necroptosis pathway including receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) were up-regulated in 3-MCPD-dipalmitate-induced acute kidney injury (AKI). Deletion of RIPK3 or MLKL, and inhibition of RIPK1 suppressed AKI. The up-regulation of inflammatory cytokines in the kidney of 3-MCPD-dipalmitate treated mice were attenuated in RIPK3- or MLKL- deficient mice, suggesting a positive feedback loop involving necroptosis and inflammation. The microRNA analysis revealed that 38 known miRNAs and 40 novel miRNAs were differentially expressed (DE) in the kidney treated with 3-MCPD-dipalmitate. Of these miRNAs, miR-223-3p was significantly up-regulated during 3-MCPD-dipalmitate-induced AKI. In cultured mouse proximal tubular cells, a miR-223-3p mimic suppressed RIPK3 expression, which was blocked by miR-223-3p inhibitor. The luciferase reporter assay confirmed that miR-223-3p was able to inhibit RIPK3 expression by targeting the 3' un-translated region of RIPK3. These results suggest that necroptosis contributes to 3-MCPD-dipalmitate-induced acute kidney injury, and that may be attenuated by miR-223-3p.