Study On Kidney Protection Of Betaine And Its Mechanisms In Hyperuricemic Mice

Uric acid is the final product of purine metabolism in humans. It is mainly excreted from the body through the kidney by renal organic ion transporters (approximately2/3). And there is still a small part of uric acid excreted from the body through the intestinal (about 1/3). The over-production of uric acid and/or under-excretion of uric acid results in high serum uric acid levels, hyperuricemia. Hyperuricemia is detrimental to human health, which causes the development of gout, cardiovascular diseases, metabolic syndrome, renal dysfunction and injury. Therefore, it is necessary to study the pathological mechanism of hyperuricemia, as well as provide a new way of the prevention and treatment for hyperuricemia and its related diseases, being important theoretical and practical value.Betaine (N, N, N-trimethylglycine) is distributed widely in animals, plants and microorganisms. Its synthesis and accumulation are triggered in these organisms induced by drought, high salinity or temperature. Betaine with a methyl donor involve methylation reaction in the body. Betaine is confirmed to decrease serum uric acid concentrations in male broilers and prevent carbon tetrachloride-induced nephrotoxicity of rats. However, little is known about the contribution of renal organic ion transporters to betaine-mediated anti-hyperuricemic and nephroprotective actions in hyperuricemia. In this study, we investigated the effects of betaine on high serum uric acid levels and kidney dysfunction in potassium oxonate-induced hyperuricemic mice, as well as explored pharmacological mechanisms by detecting renal protein levels of organic ion transporters.In this study, hyperuricemia of Kunming mice was induced by intragastric administration with 250 mg/kg/d potassium oxonate, then followed by intragastric administration with 5,10,20 and 40 mg/kg betaine and 20 mg/kg benzbromarone (positive control) 1h later. Normal group was given saline (10 ml/kg). The increased levels of serum uric acid (Sur)、serum creatinine (Scr)、blood urea nitrogen (BUN) and the decreased levels of urine uric acid (Uur), fraction excretion of uric acid (FEUA) were detected in hyperuricemic mice. The increased urine levels of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) were also obviously in this animal animals. These results indicate that potassium oxonate-induced hyperuricemia is associated with renal dysfunction. Betaine was found to reverse those adverse effects in hyperuricemic mice, demonstrating that betaine has anti-hyperuricemic and nephroprotective actions.Furthermore, potassium oxonate induced expression alterations of renal urate-related proteins such as over-expression of uric acid transporters 1 (mURATl) and glucose transporter 9 (mGLUT9), and down-expression of organic anion transporters 1 (mOAT1) and ATP-binding cassette G member 2 (mABCG2) at protein levels in hyperuricemic mice. Betaine was found to down-regulate mURAT1 and mGLUT9 protein levels and up-regulate mOAT1 and mABCG2 protein levels in this animal model, which were consistent with the elevation of FEUA.These results suggest that betaine may improve hyperuricemia by inhibiting reabsorption of uric acid and promote the excretion of uric acid in the kidney of hyperuricemic mice.Moreover, hyperuricemic mice were found to develop expression reductions of renal organic cation transporters 1/2 (OCT1/2) and organic cation/carnitine transporters 1/2 (OCTN1/2) at protein levels. These data suggest that hyperuricemia condition may affect the function of kidney transportation for organic ion in animals, which may cause accumulation of these ions and in turn aggravate renal injury. Betaine could up-regulate OCT1 and OCTN1/2 expressions, and be able to show its renal protection.The findings from this study provide the experimental and theoretical basis that betaine has anti-hyperuricemic and nephroprotective actions in hyperuricemia.