The Metabonomics Study Of Hyperuricemia And The Construciton Of Uric Acid Nephropathy Animal Model

Hyperuricemia,as one kind of metabolic diseases,was due to the mechanism of the excessive production or the decreased renal excretion of uric acid,and its prevalence has been increasing year by year.Hyperuricemia is closely associated with gout,renal dysfunction, cardiovascular disease, hypertension, hyperlipidemia, insulin resistance, diabetes, metabolic syndrome.As a kind of system biology,metabonomics focus on the changes of endogenous small molecules in vivo, which is often used to study the pathogenesis, screen the early biomarkers of diseases and pharmacological activities of Chinese traditional medicine,and it has a unique advantage in the study of metabolic diseases.Traditionally, hyperuricemia was often only considered as a marker of renal dysfunction,but recent studies suggest that uric acid plays an important role in the initiation or progression of kidney diseases,and is believed an independent risk factor.The uricosuric agents of western medicine in clinical practice had produced some undesirable side effects,therefore, the development of safer and more effective hypouricemic agents is highly warranted. Thus, the relationship between uric acid and kidney diseases and urgent need of available anti-hyperuricemic agents aroused people's great interest.Traditional herbal medicines, as a treasure of the Chinese nation, has been used for treatment of hyperuricemia and gout since ancient times. The uric acid nephropathy animal model induced by hyperuricemia is not only the basis of the study on the relationship between hyperuricemia and uric acid nephropathy but also the screening of uricosuric drug and the evaluation of drug efficacy.In this study, we firstly use the metabolomics approach to study hyperuricemia rat model induced by uricase inhibitor potassium oxonate.Then,the uric acid nephropathy animal models induced through the methods of administration of different dosage, different administration period of potassium oxonate or combinative administration of potassium oxonate and uric acid were attempted to provide the thinking and reference for the related researchs.1. The different dosages of potassium oxonate(250mg/kg,500mg/kg),a uricase inhibitor were used to induce hyperuricemia in mice intraperitoneally.The hyperuricemia model was successfully induced at the dose of 500mg/kg. A metabonomics approach based on ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was developed to analysis the serum of mice,21 metabolites were identified as potential biomarkers which involved in amino acid metabolism, lipids metabolism, energy metabolism, and so on.2. The different dosages of potassium oxonate(250mg/kg,400mg/kg) by gavage for one week, were used to induce hyperuricemia in mice. The hyperuricemia model was successfully induced when the dosage is 400mg/kg.The uric acid nephropathy animal models can't be constructed successfully although the levels of creatinine and urea nitrogen of two model groups increased, which were not statistically significant compared with the control group.3. The potassium oxonate were used to induce hyperuricemia in mice by gavage for two weeks, three weeks,respectively.Compared with the control group, the content of uric acid in the two model groups were significantly higher than that in the control group,which suggested that hyperuricemia model is successful.The levels of creatinine,urea nitrogen in the model groups were all decreased, and urea nitrogen levels were significantly different, and there were significant different in the high dose model group from the control group.4. The hyperuricemia model was induced by administering potassium oxonate and uric acid by gavage for one week. The results indicated that the serum uric acid leves of models induced by potassium oxonate combined with the uric acid dose of 500mg/kg and 250mg/kg were higher than that in the control group, but there was no significant difference.By contrast, the uric acid values of high dose model group induced by potassium oxonate combined with the uric acid dose of 1000mg/kg were significantly different from the control group, which indicated that the hyperuricemia model was successful. But all of the model groups had no significant change in the levels of creatinine, urea nitrogen compared with the control group.In this study, we use the uricase inhibitor potassium oxonate to successfully induce hyperuricemia model, the administration of potassium oxonate by gavage is better, and the dose of oral administration was maintained at 300 to 400mg/kg. Using the method of metabonomics, the study of hyperuricemia was carried out, and the 21 biomarkers were found to understand the relationship between hyperuricemia and other diseases.,which can be as early biomarkers of disease.The uric acid nephropathy animal models can't be induced through the methods of administration of different dosage,different administration period of potassium oxonate or combinative administration of potassium oxonate and uric acid,which provide the thinking and reference for the related research.