Establishment and optimization of a novel mouse model of hyperuricemic nephropathy

Abstract

Hyperuricemia is a metabolic disorder characterized by elevated serum uric acid levels. Soluble urate can activate immune responses, and the excessive accumulation of urate in the kidneys results in hyperuricemic nephropathy (HN). However, the lack of an established HN model is a major obstacle to advancing research into the pathogenesis of HN and the development of novel drugs. In this study, we generated and evaluated an optimized mouse model of HN by the combined administration of potassium oxonate and hypoxanthine at various dosages. Our results demonstrated that intraperitoneal injection of 200 mg/kg potassium oxonate with gavage of 500 mg/kg hypoxanthine caused renal injury in mice, as evidenced by the elevation in serum uric acid, serum creatinine, and 24 h albuminuria levels, as well as pathological changes in renal histology. Intraperitoneal injection of 200 mg/kg potassium oxonate with gavage of 500 mg/kg hypoxanthine markedly increased the production of uric acid, inhibited uricase activity, and disrupted uric acid transporters. This led to supersaturated urate deposition in the kidneys, triggering renal inflammation and fibrosis, thereby promoting HN progression. In conclusion, we successfully established a stable and efficient mouse model that can mimic the pathogenesis of HN. This novel model may facilitate the discovery of therapeutic targets and the development of new drugs for the treatment of HN.

Keywords

• Animal model
• fibrosis
• hyperuricemic nephropathy
• hypoxanthine
• inflammation
• potassium oxonate