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Renal Hemodynamics: Biomolecular Control Mechanisms and Integration of Vascular and Tubular Function

Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome

Departments of ¹Nephrology and ²Pathology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico; ³Nephrology, Hypertension and, Transplantation, University of Florida, Gainesville, Florida; and ⁴TAP Pharmaceutical Products, Incorporated, Lake Forest, Illinois

Submitted 2 October 2007 ; accepted in final form 23 January 2008

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.

hyperuricemia; glomerular hypertension; arteriolopathy

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