Background: Xanthine oxidoreductase (XOR) produces superoxide along with uric acid. This reactive oxygen species induces organ damage. Therefore, we aimed to investigate whether XOR-induced superoxide is associated with renal abnormality in diabetic mice.
Methods: Db/db mice (9-week-old) were fed standard diets with or without topiroxostat (1, 3, and 10 mg/kg/day) or febuxostat (3, 10, 30, and 45 mg/kg/day) for 4 weeks. Furthermore, topiroxostat (1 and 3 mg/kg/day) and febuxostat (3 mg/kg/day) were administered for 7 days or 8 weeks. The levels of urinary albumin excretion (UAE), monocyte chemoattractant protein-1 (MCP-1), and angiotensin II were determined. For renal pathological or mechanistic analysis, periodic acid-Schiff (PAS), nitrotyrosine, and MCP-1 staining or renal gene expression, XOR activity, and purine body levels were evaluated.
Results: Both topiroxostat and febuxostat suppressed UAE : topiroxostat 3 mg/kg/day, 11.5 ± 33 μg/day versus vehicle 253.7 ± 69 μg/day, p<0.05; febuxostat 3 mg/kg/day, 255 ± 92 μg/day versus vehicle 634 ± 101 μg/day, p=0.05, for 4 weeks, respectively, and reduced immunohistological staining of enhanced oxidative stress and inflammation markers without affecting glycated hemoglobin. Topiroxostat but not febuxostat decreased urinary MCP-1 and angiotensin II levels and attenuated morphological hypertrophy in the glomerulus and epithelial cell enlargement (diameter and height) in the proximal tubules. In the early stage, topiroxostat and febuxostat decreased renal XOR activity in response to increased purine body levels (topiroxostat 3 mg/kg/day, 2.25 ± 0.19 mg/g tissue, p=0.07; febuxostat 3 mg/kg/day, 2.34 ± 0.09 mg/g tissue, p<0.05 to vehicle 2.01 ± 0.12 mg/g tissue, for 7 days) relative to the vehicle. Moreover, febuxostat upregulated the gene expression of renin 1 (Ren1) and downregulated that of adenine phosphoribosyltransferase (APRT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) compared with that of the diabetic control.
Conclusion: Topiroxostat and febuxostat exhibited renoprotective effects by suppressing oxidative stress and inflammation, and enhancing the salvage pathway via XOR inhibition.
Nakamura T, Nagao G, Nampei M, Murase T, Morimoto N, Ashizawa N, Iwanaga T, Sakamoto R
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