Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Germany.
Kidney Blood Press Res. 2013;37(4-5):240-51. doi: 10.1159/000350149. Epub 2013 Jul 14.
The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches.
The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH.
A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies. © 2013 S. Karger AG, Basel.
氧化和未氧化 PTH 的生物学特性有很大不同。氧化 PTH（oxPTH）失去了对 PTH 受体的刺激作用，而未氧化 PTH（n-oxPTH）是受体的完全激动剂。这在 20 世纪 70 年代和 80 年代的 20 多项已发表的研究中已有描述。然而，迄今为止，在开发用于临床的 PTH 检测方法时，PTH 氧化一直被忽视。即使是目前使用的第三代检测系统也不考虑 PTH 的氧化。我们最近开发了一种区分 oxPTH 和 n-oxPTH 的检测方法。在本研究中，我们为该检测系统建立了正常值。此外，我们比较了不同人群慢性肾功能衰竭患者 oxPTH 与 n-oxPTH 的比值：4C 研究中 620 名肾功能衰竭 2-4 期的儿童，342 名透析患者和 602 名肾移植受者。此外，我们使用生物物理结构方法对 oxPTH 或 n-oxPTH 与 PTH 受体的相互作用进行了建模。
与成年患者（透析患者和肾移植受者）相比，儿童的 n-oxPTH 浓度具有最高的均值和最高值。所有肾功能受损的三组人群中，个体患者 oxPTH 与 n-oxPTH 的关系差异很大。对 89 名健康对照者的 n-oxPTH 分析表明，肾功能衰竭患者的 n-oxPTH 浓度高于健康成年对照组（肾功能衰竭儿童的 2.25 倍，透析患者的 1.53 倍，肾移植受者的 1.56 倍）。然而，计算机辅助生物物理结构建模表明，oxPTH 和 n-oxPTH 的空间和/或静电变化很小。这表明 PTH 氧化可能诱导 PTH 的重折叠，从而通过 PTH 三维结构改变来改变 PTH-PTH 受体相互作用。
当前最先进的检测系统测量的循环 PTH 中，有很大一部分被氧化，因此没有生物活性。个体患者 oxPTH 与 n-oxPTH 的关系差异很大。与健康对照组相比，肾功能衰竭患者的 n-oxPTH 浓度高 1.5-2.25 倍。n-oxPTH 的测量可能更准确地反映激素状态。iPTH 测量值描述的可能是肾衰竭患者的氧化应激，而不是 PTH 激素状态。然而，这需要在进一步的临床研究中证明。© 2013 S. Karger AG，巴塞尔。
Zotero 插件