Moderate-intensity exercise attenuates bone loss in hyperuricemic nephropathic mice

Hyperuricemia (HUA) is an independent risk factor for chronic kidney disease (CKD) and can lead to hyperuricemic nephropathy (HN) with skeletal disorders and bone loss. Exercise, as a non-pharmacologic intervention, has potential value in improving bone health and slowing disease progression. However, the protective effect of exercise on HN-induced bone loss and its mechanism has not been clarified. This study aims to investigate the effects of moderate-intensity exercise on renal injury and bone microstructure in HN mice.

Thirty-two 5-week-old C57BL/6 mice were randomly divided into blank control (CON), model (HUA), exercise blank control (EX-CON), and exercise model (EX-HUA) groups. The HN model was induced by gavage of potassium oxalate (300 mg/kg) and adenine (75 mg/kg) in the HUA and EX-HUA groups. The EX-CON and EX-HUA groups were subjected to 8 weeks of moderate-intensity exercise. At the end of the experiment, serum levels of uric acid, creatinine, and urea nitrogen, as well as inflammatory factors and uric acid excretion factors in renal tissues, were detected, and then the pathological changes in the kidneys were assessed by HE staining, and the microstructures of the bones were assessed and analyzed by micro-CT, HE staining and TRAP staining. The expression of osteogenic factors (ALP, RUNX2) and bone resorption factors (MMP9, NFATC1) were detected by qPCR, Western blotting, and immunofluorescence.

Compared with the CON group, mice in the HUA group showed significantly higher serum uric acid levels, lower levels of creatinine and urea nitrogen, and pathological changes in the kidneys, such as vacuolar degeneration, nuclear detachment, and tubular atrophy. After the exercise intervention, the uric acid level of the EX-HUA group was significantly reduced, the renal function indexes were improved, and the renal pathological damage was reduced. Micro-CT results showed that the bone quality, bone density, trabecular tissue volume, trabecular number, trabecular connectivity, and trabecular thickness of the HUA group were significantly decreased, and trabecular separation was increased, whereas the exercise intervention significantly improved these bone microstructural parameters. In addition, the mRNA and protein expression levels of bone-forming factors (ALP, RUNX2) were significantly reduced in the HUA group, while the expression levels of bone resorption factors (MMP9, NFATC1) were significantly increased, and exercise intervention reversed these changes.

hyperuricemic nephropathy leads to deterioration of bone microarchitecture, dysregulation of the balance between bone formation and bone resorption, and consequent bone loss. In contrast, moderate-intensity exercise improves renal function and regulates the balance of osteogenic-osteoclastogenic cytokines, thereby attenuating renal injury and bone loss in hyperuricemic nephropathy mice.