Oxalate regulates crystal-cell adhesion and macrophage metabolism via JPT2/PI3K/AKT signaling to promote the progression of kidney stonesOA

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 micro-tubule associated homolog 2(JPT2)is a critical molecule in Ca2+mobilization,and its intrinsic mecha-nism 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 theJPT2 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.Tran-scriptomic 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 produc-tion 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 in-flammatory polarization via JPT2/PI3K/AKT signaling.