局部TGF-β上调导致挤压综合征小鼠肾小管Na + -K + atp酶和高钾血症降低

S. Mizuno, Y. Mizuno-Horikawa
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引用次数: 1

摘要

高钾血症是挤压综合征合并横纹肌溶解患者最重要的危险因素之一。甘油注射动物已被用作横纹肌溶解引起的急性肾损伤(AKI)的实验模型,但关于高钾血症的发病和分子机制的信息很少。在我们的小鼠模型中,在肌肉和肾脏损伤的进展过程中,单次注射50%甘油溶液(10 ml/kg, i.m)后,血浆钾水平升高。肾小管Na+-K+- atp酶作为离子交换泵从血液中清除钾进入肾小管上皮细胞。肾组织化学显示肾小管Na+-K+- atp酶表达明显下降,特别是在我们的AKI模型中甘油刺激后24小时。与活性Na+-K+- atp酶的丧失相反,肾脏中转化生长因子-β (TGF-β)的水平显著增加,TGF-β已知在体外抑制Na+-K+- atp酶的产生。甘油刺激小鼠后给予抗tgf -β抗体,可部分恢复对肾Na+-K+- atp酶活性的抑制。结果,TGF-β-中和的AKI小鼠高钾血症得到改善,血浆钾浓度显著降低。综上所述,我们预测内源性TGF-β是抑制Na+-K+- atp酶产生的关键调节因子,并在一定程度上增强横纹肌溶解诱导AKI进展过程中的高钾血症。据我们所知,这是首次报道确定内源性TGF-β在挤压综合征期间肾钾代谢中的关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na + -K + ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome
Hyperkalemia is one of the most important risk factors in patients suffering from crush syndrome with rhabdomyolysis. Glycerol-injected animals have been used as an experimental model of rhabdomyolysis-induced acute kidney injury (AKI), but little information is available for the onset and molecular mechanism of hyperkalemia. In our murine model, plasma potassium levels increased after a single injection of 50%-glycerol solution (10 ml/kg, i.m.) during the progression of muscular and renal injuries. Renal tubular Na+-K+-ATPase functions as ion-exchange pomp for potassium clearance from blood into renal tubular epithelial cells. Renal histochemistry revealed an apparent decrease in the tubular Na+-K+-ATPase expression, especially at 24 hours post-glycerol challenge in our AKI model. In contrast to the loss in active Na+-K+-ATPase, there was a significant increase in the renal levels of transforming growth factor-β (TGF-β) that is known to suppress Na+-K+-ATPase production in vitro. When anti-TGF-β antibody was administered in mice after the glycerol challenge, the suppression of renal Na+-K+-ATPase activity was partially restored. As a result, hyperkalemia was improved in the TGF-β-neutralized AKI mice, associated with a significant decrease in plasma potassium concentration. Taken together, we predict that endogenous TGF-β is a key regulator for inhibiting Na+-K+-ATPase production and, in part, enhancing hyperkalemia during progression of rhabdomyolysis-induced AKI. This is, to our knowledge, the first report to determine a critical role of endogenous TGF-β in renal potassium metabolism during crush syndrome.
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