草酸盐是一种有机二羧酸,是植物性食品的常见成分。肾脏是草酸盐排泄的重要器官,但是过量的草酸盐可能会诱发肾结石。木星微管相关同源物2(JPT2)是Ca2+动员的关键分子,其在草酸盐暴露和肾结石中的内在机制尚不清楚。本研究旨在揭示JPT2在草酸盐暴露和肾结石中的作用机制。遗传方法用于控制JPT2在细胞和小鼠中的表达,使用转录组学和非靶向代谢组学分析了JPT2的作用机制。结果表明,草酸暴露引发了JPT2的上调,这参与了烟酸腺嘌呤二核苷酸磷酸(NAADP)介导的Ca2动员。转录组分析显示,JPT2敲低抑制细胞粘附和巨噬细胞炎症极化,这些主要由磷脂酰肌醇3-激酶(PI3K)/AKT信号传导,分别。非靶向代谢组学表明JPT2敲低抑制巨噬细胞中琥珀酸半醛(SSA)的产生。此外,小鼠JPT2缺乏抑制肾结石矿化。总之,这项研究表明,草酸盐暴露通过促进晶体细胞粘附来促进肾结石,并通过JPT2/PI3K/AKT信号调节巨噬细胞代谢和炎症极化。
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 Ca2+ 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 Ca2+ mobilization. Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown, and these were dominated by phosphatidylinositol 3-kinase (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.