Abstract
Chronic kidney disease (CKD) is acknowledged as one of the largest public health problems in the world, characterized by a complex and diverse pathogenesis. Adenine-induced CKD, a classical model with multiple injury mechanisms, has been extensively employed in CKD research. However, the complete elucidation of the mechanisms underlying adenine-induced CKD remains elusive. In this study, the impacts of adenine (200 mg/kg/day) intake on the urine metabolome of rats were initially investigated using non-targeted metabolomics, and then targeted metabolomics was used to quantitatively verify key metabolites on crucial metabolic pathways. Interestingly, the interconnectedness of two significant pathways was discovered and validated through molecular biology techniques. The results found that adenine can cause significant perturbations in purine metabolism and the biosynthetic pathways of phenylalanine, tyrosine, and tryptophan. Subsequent targeted metabolomic analysis revealed a significant reduction in amino acid and hypoxanthine and creatinine levels in the kidneys of CKD rats, accompanied by an increase in xanthine level. Further analysis found that purine pathway can increase ROS production and affect the level of aromatic amino acid transporter SLC7A5, thus influencing the biosynthesis pathway of phenylalanine, tyrosine and tryptophan, ultimately contributing to kidney injury. This discovery provides offers novel insights into the underlying pathological mechanism of adenine-induced CKD. The development of chronic kidney disease is induced by multiple pathways of aromatic amino acid metabolism and purine metabolism.