A Novel Mouse Model of Hyperuricemia and Gouty Nephropathy
Hyperuricemia, characterized by elevated serum uric acid levels due to overproduction or underexcretion of uric acid, is the second most common metabolic disease in China, following diabetes mellitus. Recent studies have highlighted its role in renal tubular injury, subsequent tubulointerstitial fibrosis, and the development of gouty nephropathy. Despite its clinical significance, the lack of a suitable and stable mouse model has hindered the advancement of research into the mechanisms and treatment of hyperuricemia and gouty nephropathy. This study aimed to develop a novel mouse model to address this gap.
The study utilized male C57BL/6J mice weighing approximately 30 grams, which were randomly divided into three groups: a control group treated with carboxymethyl cellulose sodium (CMC-Na) alone, a group treated with 100 mg/kg adenine and 500 mg/kg potassium oxonate (Ade-100 + OXO-500), and a group treated with 150 mg/kg adenine and 300 mg/kg potassium oxonate (Ade-150 + OXO-300). The mice were administered the treatments intragastrically daily for three weeks. Parameters such as food intake, water consumption, and weight gain were measured before administration. Blood samples were collected weekly to measure serum uric acid and creatinine levels. On the final day of the experiment, 24-hour urine samples were collected to determine urinary uric acid and protein levels. The mice were then sacrificed, and blood and kidney tissues were harvested for biochemical and histological analyses.
The results demonstrated that mice treated with adenine and potassium oxonate exhibited severe kidney injury, as indicated by elevated serum creatinine levels starting from the seventh day of the study. Elevated serum uric acid levels at the second and third weeks confirmed the successful establishment of the hyperuricemia mouse model. The treatment significantly decreased body weight gain and food intake while increasing water intake and 24-hour urine volume. Serum xanthine oxidase activity, a key enzyme in uric acid production, was significantly upregulated in the Ade-100 + OXO-500 group, leading to a decrease in urinary uric acid levels.
Histological examination of the kidneys revealed significant damage in the treated groups, including dilated kidney tubules, ectatic Bowman spaces, and the presence of dark needle-like urate crystals. Focal tubulointerstitial fibrosis and glycometabolic disorder were also evident, particularly in the Ade-100 + OXO-500 group. Immunohistochemistry showed massive accumulation of URAT1 and GLUT9 in injured tubules, indicating increased uric acid reabsorption in the proximal renal tubules. Western blotting confirmed the increased renal expression of URAT1 and GLUT9 in the treated mice, with higher levels observed in the Ade-100 + OXO-500 group.
The study also assessed the effects of adenine and potassium oxonate on systemic inflammation by measuring serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Both cytokines were significantly elevated in the treated mice, with the Ade-100 + OXO-500 group exhibiting more severe inflammation. These findings suggest that the Ade-100 + OXO-500 treatment is more effective in generating disease phenotypes of hyperuricemia and gouty nephropathy in mice.
The development of this mouse model addresses the limitations of previous hyperuricemia models, which often suffered from issues such as inaccurate dosing, high mortality rates, and low reproducibility. The combination of adenine and potassium oxonate in this study effectively increased purine intake and inhibited uricase activity, leading to elevated serum uric acid levels and the development of hyperuricemia and gouty nephropathy.
In conclusion, this study successfully established a novel mouse model of hyperuricemia and gouty nephropathy by administering adenine and potassium oxonate. The model was validated through serologic pathology, renal tissue histology, expression of uric acid transporters, and inflammatory factors. This animal model provides a valuable tool for evaluating the efficacy of therapeutic agents and furthering research into the pathogenesis and treatment of hyperuricemia and gouty nephropathy.
doi.org/10.1097/CM9.0000000000000964
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