The synergic renoprotective effect of Rehmanniae Radix Preparata and Corni Fructus on adenine-induced chronic kidney disease rats based on integrated plasma metabolomics and network pharmacology approach

Rehmanniae Radix Preparata (RR) and Corni Fructus (CF) are commonly used together for the treatment of chronic kidney disease (CKD) in the clinical practices for thousands of years. However, little information on their synergy mechanism is available. In this study, an integrated approach combining ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based metabonomics and network pharmacology was adopted to elucidate the cooperation mechanism of RR and CF on the amelioration of CKD. Furthermore, the targets from network pharmacology and metabolism pathways were jointly analyzed. Finally, the activities of key metabolic enzymes were experimentally validated by ELISA. Metabolic profiling indicated that the metabolic disturbance in plasma was markedly alleviated after treatment. Nine putative biomarkers mainly involving in phenylalanine, tyrosine and tryptophan biosynthesis and tyrosine metabolism were identified. Moreover, the compound-target-pathway network of RR and CF for CKD treatment was constructed by network pharmacology, which was related to tyrosine metabolism and arginine and proline metabolism. The results were partly consistent with the findings of plasma metabolomics. In conclusion, this study solidly supported and enhanced current understanding of the synergy effects of RR and CF on CKD. Meanwhile, it also confirmed the feasibility of combining metabolomics and network pharmacology to identify active components and elucidate the pharmacological effects of traditional Chinese medicines (TCMs).