Department of Medical Cell Biology, Uppsala University, Sweden.
Am J Physiol Renal Physiol. 2010 Aug;299(2):F380-6. doi: 10.1152/ajprenal.00175.2010. Epub 2010 Jun 2.
In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.
除了引起尿毒症症状外，尿毒症毒素还会加速肾衰竭的进展。为了阐明尿毒症状态的病理生理学机制，我们研究了代表性尿毒症毒素——硫酸吲哚酚（IS）对肾小管细胞氧代谢的影响。我们发现在新鲜分离的大鼠和人近端肾小管中，IS 会增加氧消耗。利用哇巴因（Na-K-ATP 酶抑制剂）和 apocynin（NADPH 氧化酶抑制剂）以及体内基因沉默方法敲除 p22(phox) 的研究表明，IS 引起的肾小管氧消耗增加依赖于 Na-K-ATP 酶和氧化应激。我们研究了增强的氧消耗是否导致肾脏随后缺氧。给予吲哚的大鼠血清 IS 浓度增加与肾脏氧合作用降低（8 小时）相关。16 周时，残余肾脏发生缺氧。用 AST-120（一种去除尿毒症毒素的口服吸附剂）治疗大鼠，降低了血清 IS 水平并改善了肾脏的氧合作用。残余肾脏缺氧的改善与更好的肾功能和较少的组织损伤相关。血清 IS 水平的降低也导致肾脏氧化应激减少。我们的离体和体内研究表明，尿毒症状态可能通过调节肾小管细胞的氧代谢而使肾功能恶化。尿毒症毒素引起的肾小管细胞异常氧代谢至少部分是由氧化应激介导的。
