Metabolic and Network Pharmacological Analyses of the Therapeutic Effect of Grona styracifolia on Calcium Oxalate-Induced Renal Injury

Grona styracifolia (Osbeck) Merr. (GS), a popular folk medicine, is clinically applied to treat nephrolithiasis. In this study, a urinary metabolic analysis was performed in a mouse model of renal calcium oxalate (CaOx) crystal deposition to identify the differentially altered metabolites in mice with oxalate-induced renal injury and explore the therapeutic mechanisms of GS against nephrolithiasis. Twenty-four mice were randomly divided into the control, oxalate and GS-treated groups. A metabolomics approach based on ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to analyze the metabolic profiles of the urine samples. In addition, network pharmacology analysis was performed with different databases. As a result, the protective effects of GS were verified by measuring biochemical parameters and detecting crystal deposition. Fifteen metabolites were identified as the differentially altered metabolites in mice with crystal-induced renal injury. Most were involved in amino acid and fatty acid metabolism. Thirteen of these metabolites showed a reversal trend following GS treatment. A component-target-metabolite network was further constructed and nine overlapping target proteins of GS and the differentially altered metabolites were discovered. Among these proteins, the expression of estrogen receptor 2 (ESR2) in renal tissues was significantly down-regulated while androgen receptor (AR) expression was obviously increased in the oxalate group compared with the control group. These changes were reversed by the GS treatment. In conclusion, GS exerts its therapeutic effect by regulating multiple metabolic pathways and the expression of ESR and AR in mice with oxalate-induced renal injury.

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