Involvement of the NADPH oxidase 2 pathway in renal oxidative stress in Aqp11-/- mice
Involvement of the NADPH oxidase 2 pathway in renal oxidative stress in Aqp11-/- mice
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DOI：
10.1016/j.bbrep.2019.01.003
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发表时间：
2019-03-01
影响因子：
2.7
通讯作者：
Ikeda, Masahiro
中科院分区：
文献类型：
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作者：
Hoshino, Yuya;Sonoda, Hiroko;Ikeda, Masahiro
Aquaporin-11 (AQP11) 是一种细胞内 AQP。几项针对 Aqp11(-/-) 小鼠的研究表明，AQP11 在出生后肾脏的正常发育中发挥作用。我们之前的研究表明，氧稳态的改变可能与 AQP11 缺乏引起的肾损伤有关，尽管其潜在机制尚不清楚。为了澄清这个问题，我们检查了 Aqp11(-/-) 小鼠中与氧稳态相关的基因。在涉及氧稳态的 62 个基因中，与野生型小鼠相比，Aqp11(-/-) 小鼠中有 35 个基因上调超过 2 倍。使用这些基因的途径分析提取了负责巨噬细胞中活性氧产生的途径。由于参与 NADPH 氧化酶 2 (NOX2) 复合物的基因表达显着增加超过 14 倍，我们在蛋白质水平上进一步分析了 NOX2。免疫印迹分析显示Aqp11(-/-)小鼠肾脏中NOX2蛋白显着增加，免疫组织化学显示肾间质中NOX2蛋白和巨噬细胞标记蛋白增加。这些结果表明NOX2诱导的氧化应激伴随巨噬细胞浸润在Aqp11(-/-)小鼠氧稳态的改变中发挥重要作用。
Aquaporin-11 (AQP11) is an intracellular AQP. Several studies with Aqp11(-/-) mice have shown that AQP11 has a role in normal development of the kidney after birth. Our previous studies have suggested that alteration of oxygen homeostasis may be involved in the kidney injury caused by AQP11 deficiency, although the underlying mechanism is largely unknown. To clarify this issue, we examined genes that are related to oxygen homeostasis in Aqp11(-/-) mice. Among 62 genes that are involved in oxygen homeostasis, 35 were upregulated by more than 2-fold in Aqp11(-/-) mice in comparison with wild-type mice. Pathway analysis using these genes extracted the pathway responsible for production of reactive oxygen species in macrophages. As expression of the genes involved in the NADPH oxidase 2 (NOX2) complex was dramatically increased by more than 14-fold, we further analyzed NOX2 at the protein level. Immunoblotting analysis demonstrated a dramatic increase of NOX2 protein in the kidney of Aqp11(-/-) mice, and immunohistochemistry showed that NOX2 protein and a marker protein for macrophages were increased in the renal interstitium. These results indicate that NOX2-induced oxidative stress accompanied by macrophage infiltration plays an important role in alteration of oxygen homeostasis in Aqp11(-/-) mice.