Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.

译文

尽管高尿酸血症已被证明与心血管疾病和慢性肾脏疾病 (CKD) 的进展有关,但关于黄嘌呤氧化酶 (XO) 抑制剂是否除了降低血清尿酸水平外还具有器官保护作用,存在相互矛盾的证据。在这项研究中,我们讨论了XO抑制在患有高尿酸血症的啮齿动物CKD模型中的心肺作用。Sprague-Dawley大鼠接受5/6肾切除术,并接受尿酸酶抑制剂oxonic酸治疗8周 (rk   +  HUA大鼠)。在某些大鼠中,口服XO抑制剂非布索坦。与对照组相比,rk   +  HUA组蛋白尿和肾损伤明显增加。非布索坦可降低血清尿酸和尿白蛋白水平。肾脏的组织学和免疫组织化学分析表明,非布司他减轻了rk   hua hua大鼠的肾小球,肾小管间质和小动脉损伤。此外,在心脏中,rk   +  HUA表现为单个肌纤维肥大和心脏纤维化,非布沙坦明显减弱。我们发现肾损伤与心脏变化的指标具有良好的相关性,从而证实了该模型中的心-肾相互作用。最终,NF-E2-related因子2 (Nrf2) 和下游靶血红素oxygenase-1 (HO-1) 蛋白在rk   +  HUA大鼠心脏和肾脏中的水平均升高,非布沙坦缓解了这些变化,提示该治疗减轻了组织氧化应激负荷。这些数据表明,非布索坦可预防rk   hua hua大鼠的心脏和肾脏损伤,并强调了XO在心肺相互作用中的病理重要性。

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