Abstract
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.
Highlights
Kidney stone disease, known as nephrolithiasis, is a common disease jeopardizing the health of 7–13% of the population worldwide (Sorokin et al, 2017)
Each relative standard derivation (RSD) value of the peak area was below 3.2%, as shown in Table 1, which indicated that the UHPLC-Q-TOF system was stable and repeatable and that the extraction of Grona styracifolia Merr (GS) was reproducible and reliable
More information about the tandem mass spectrometry (MS/MS) is provided in the Supplemental Materials section (Supplementary Figure S1)
Summary
Known as nephrolithiasis, is a common disease jeopardizing the health of 7–13% of the population worldwide (Sorokin et al, 2017). Nephrolithiasis is considered a systemic disease because of its significant association with chronic kidney disease, cardiovascular events and metabolic syndrome (including type 2 diabetes, obesity, hypertension and dyslipidemia), as reported by numerous epidemiological studies (Sakhaee, 2008). Calcium oxalate (CaOx) is the most common inorganic matrix found in kidney stones and crystals. CaOx crystals, an early form of kidney stones, have been shown to cause apoptosis in renal tubular cells (Mulay et al, 2013). Renal injury induced by kidney stones has been observed throughout the process of stone formation. Metabolic disturbances are promoted by crystal-induced renal injury. Metabolic disturbances resulting from renal injury during crystal formation should be addressed
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