Sánchez-Lozada Laura G, Tapia Edilia, Bautista-García Pablo, Soto Virgilia, Avila-Casado Carmen, Vega-Campos Iliana P, Nakagawa Takahiko, Zhao Lin, Franco Martha, Johnson Richard J
Dept. of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Juan Badiano 1, 14080 Mexico City, Mexico.
Am J Physiol Renal Physiol. 2008 Apr;294(4):F710-8. doi: 10.1152/ajprenal.00454.2007. Epub 2008 Jan 23.
Increased fructose consumption is associated with hyperuricemia, metabolic syndrome, and renal damage. This study evaluated whether febuxostat (Fx), an investigational nonpurine, and selective xanthine oxidase inhibitor, could alleviate the features of metabolic syndrome as well as the renal hemodynamic alterations and afferent arteriolopathy induced by a high-fructose diet in rats. Two groups of rats were fed a high-fructose diet (60% fructose) for 8 wk, and two groups received a normal diet. For each diet, one group was treated with Fx (5-6 mg.kg(-1).day(-1) in the drinking water) during the last 4 wk (i.e., after the onset of metabolic syndrome), and the other received no treatment (placebo; P). Body weight was measured daily. Systolic blood pressure and fasting plasma uric acid (UA), insulin, and triglycerides were measured at baseline and at 4 and 8 wk. Renal hemodynamics and histomorphology were evaluated at the end of the study. A high-fructose diet was associated with hyperuricemia, hypertension, as well as increased plasma triglycerides and insulin. Compared with fructose+P, fructose+Fx rats showed significantly lowered blood pressure, UA, triglycerides, and insulin (P < 0.05 for all comparisons). Moreover, fructose+Fx rats had significantly reduced glomerular pressure, renal vasoconstriction, and afferent arteriolar area relative to fructose+P rats. Fx treatment in rats on a normal diet had no significant effects. In conclusion, normalization of plasma UA with Fx in rats with metabolic syndrome alleviated both metabolic and glomerular hemodynamic and morphological alterations. These results provide further evidence for a pathogenic role of hyperuricemia in fructose-mediated metabolic syndrome.
果糖摄入量增加与高尿酸血症、代谢综合征及肾损害相关。本研究评估了非布司他（Fx），一种处于研究阶段的非嘌呤选择性黄嘌呤氧化酶抑制剂，是否能够缓解代谢综合征的特征以及高果糖饮食诱导的大鼠肾血流动力学改变和入球小动脉病变。两组大鼠给予高果糖饮食（60%果糖）8周，另外两组给予正常饮食。对于每种饮食，一组在最后4周（即代谢综合征发作后）用Fx（饮用水中5 - 6 mg·kg⁻¹·d⁻¹）治疗，另一组不接受治疗（安慰剂；P）。每天测量体重。在基线、4周和8周时测量收缩压、空腹血浆尿酸（UA）、胰岛素和甘油三酯。在研究结束时评估肾血流动力学和组织形态学。高果糖饮食与高尿酸血症、高血压以及血浆甘油三酯和胰岛素升高相关。与果糖 + P组相比，果糖 + Fx组大鼠的血压、UA、甘油三酯和胰岛素显著降低（所有比较P < 0.05）。此外，相对于果糖 + P组大鼠，果糖 + Fx组大鼠的肾小球压力、肾血管收缩和入球小动脉面积显著减小。正常饮食大鼠用Fx治疗无显著影响。总之，在代谢综合征大鼠中用Fx使血浆UA正常化可缓解代谢及肾小球血流动力学和形态学改变。这些结果为高尿酸血症在果糖介导的代谢综合征中的致病作用提供了进一步证据。
