Down-Regulation of Renal Klotho Expression by Shiga Toxin 2
Down-Regulation of Renal Klotho Expression by Shiga Toxin 2
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DOI：
10.1159/000368457
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发表时间：
2014-01-01
影响因子：
2.8
通讯作者：
Lang, Florian
中科院分区：
文献类型：
--
作者：
Feger, Martina;Mia, Sobuj;Lang, Florian
背景/目的：滋贺毒素2可引发经典溶血性尿毒症综合征（HUS），最终导致肾衰竭。Klotho是一种主要在肾脏表达的跨膜蛋白、蛋白酶和激素，参与肾脏磷酸盐排泄的调节，并具有肾脏保护作用。肾衰竭与klotho的肾消耗有关。本研究探讨了滋贺毒素2对肾脏klotho表达的影响。方法：给小鼠注射溶剂或滋贺毒素2，在代谢笼中测定尿流量和磷酸盐排泄。通过定量RT-PCR测量肾转录物水平，通过蛋白质印迹法测量肾蛋白丰度。用ELISA法测定血浆1，25（OH）（2）D-3和FGF 23浓度，用光度法测定血浆磷酸盐和尿素浓度。结果如下：滋贺毒素2治疗后，血浆尿素浓度，尿流量和肾磷酸盐排泄增加，但不增加血浆磷酸盐浓度。滋贺毒素2处理强烈降低肾组织中klotho mRNA表达和klotho蛋白丰度。滋贺毒素2处理进一步增加了肾组织中肿瘤坏死因子（TNF α）mRNA水平以及磷酸化p38 MAPK的蛋白丰度。治疗显著增加肾脏Cyp27 b1和降低肾脏Cyp24 a1 mRNA水平，而不显著改变血浆1，25（OH）（2）D-3水平。滋贺毒素2处理后进一步增加血浆FGF 23浓度。结论：滋贺毒素2处理刺激TNF α转录，下调肾klotho表达并增加FGF 23形成，这些作用可能有助于肾组织损伤。版权所有（C）2014 S. Karger AG，巴塞尔
Background/Aims: Shiga toxin 2 may trigger classical hemolytic uremic syndrome (HUS) eventually leading to renal failure. Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney is involved in the regulation of renal phosphate excretion and also retains renal protective effects. Renal failure is associated with renal depletion of klotho. The present study explored the influence of Shiga toxin 2 on renal klotho expression. Methods: Mice were injected with either solvent or Shiga toxin 2 and urinary flow rate and phosphate excretion were determined in metabolic cages. Renal transcript levels were measured by quantitative RT-PCR and renal protein abundance by Western blotting. Plasma concentrations of 1,25(OH)(2)D-3 and FGF23 were determined by ELISA and plasma phosphate and urea concentrations by photometry. Results: Shiga toxin 2 treatment was followed by increase of plasma urea concentration, urinary flow rate and renal phosphate excretion but not of plasma phosphate concentration. Shiga toxin 2 treatment strongly decreased klotho mRNA expression and klotho protein abundance in renal tissue. Shiga toxin 2 treatment further increased tumor necrosis factor (Tnf alpha) mRNA levels, as well as protein abundance of phosphorylated p38 MAPK in renal tissue. The treatment significantly increased renal Cyp27b1 and decreased renal Cyp24a1 mRNA levels without significantly altering plasma 1,25(OH)(2)D-3 levels. Shiga toxin 2 treatment was further followed by increase of plasma FGF23 concentrations. Conclusion: Shiga toxin 2 treatment stimulated Tnf alpha transcription, down-regulated renal klotho expression and increased FGF23 formation, effects presumably contributing to renal tissue injury. Copyright (C) 2014 S. Karger AG, Basel