Oxalate is an organic dicarboxylic acid that is a common component of plant foods. The kidneys are essential organs for oxalate excretion, but excessive oxalates may induce kidney stones. Jupiter microtubule associated homolog 2 (JPT2) is a critical molecule in Ca mobilization, and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear. This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones. Genetic approaches were used to control JPT2 expression in cells and mice, and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics. The results showed that oxalate exposure triggered the upregulation of JPT2, which is involved in nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca mobilization. Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown, and these were dominated by PI3K/AKT signaling, respectively. Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde (SSA) in macrophages. Furthermore, JPT2 deficiency in mice inhibited kidney stones mineralization. In conclusion, this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion, and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.

中文翻译：

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草酸盐通过 JPT2/PI3K/AKT 信号调节晶体细胞粘附和巨噬细胞代谢促进肾结石进展

草酸盐是一种有机二羧酸，是植物性食品的常见成分。肾脏是排泄草酸盐的重要器官，但草酸盐过多可能会诱发肾结石。木星微管相关同系物 2 (JPT2) 是 Ca 动员的关键分子，其在草酸盐暴露和肾结石中的内在机制仍不清楚。本研究旨在揭示JPT2在草酸盐暴露和肾结石中的作用机制。使用遗传方法控制细胞和小鼠中的 JPT2 表达，并使用转录组学和非靶向代谢组学分析 JPT2 的作用机制。结果表明，草酸盐暴露触发了 JPT2 的上调，JPT2 参与烟酸腺嘌呤二核苷酸磷酸 (NAADP) 介导的 Ca 动员。转录组分析显示，JPT2 敲低可抑制细胞粘附和巨噬细胞炎症极化，而这些分别由 PI3K/AKT 信号传导主导。非靶向代谢组学表明 JPT2 敲除抑制巨噬细胞中琥珀酸半醛 (SSA) 的产生。此外，小鼠体内 JPT2 缺乏会抑制肾结石矿化。总之，这项研究表明，草酸盐暴露可通过促进晶体细胞粘附、通过 JPT2/PI3K/AKT 信号传导调节巨噬细胞代谢和炎症极化来促进肾结石的形成。