Induction of Connective Tissues Damage Accompanied by Uremia

在尿毒症患者中，通过同时降解，从尿素产生大量氰酸盐。我们发现氰酸酯与脱氢抗坏血酸在生理条件下发生了一种新的反应，生成了氨甲酰化脱氢抗坏血酸衍生物（CDA）。通过对CDA结构的研究，推测CDA是一种新的生物活性物质。建立了生物样品中CDA的测定方法。当我们将本方法应用于包括血浆和尿液的生物流体时，似乎CDA存在于从正常人收集的尿液样品中。建立了同时测定生物样品中抗坏血酸和脱氢抗坏血酸的方法。利用这种方法，我们研究了氰酸盐对体内抗坏血酸-脱氢抗坏血酸氧化还原循环的影响。因此，我们发现了一个事实，氰酸盐导致在氧化应激下的生物体中的抗坏血酸耗尽。一般来说，尿毒症患者由于肾间质细胞合成的促红细胞生成素缺乏而导致贫血。红细胞在氧化性物质的解毒中起着重要作用，因此红细胞的减少是氧化应激的原因。这些事实表明，从尿素产生的氰酸盐通过上述机制降低体内抗坏血酸水平。抗坏血酸是结缔组织细胞合成胶原蛋白的必需元素。抗坏血酸缺乏是尿毒症患者脆弱结缔组织形成的一个可能因素。

In the patients with uremia, a high amount of cyanate is produced from urea through the simultaneous degradation. We found a novel reaction between cyanate and dehydroascorbate under physiologic conditions, producing carbamylated dehydroascorbate derivative (CDA), Through the investigations on the structure of CDA, it appeared to be a novel biological substance. We established a method for the determination of CDA in biological samples. When we applied the present method to biological fluids including plasma and urine, it appeared that CDA exists in the urine samples collected from the normal humans. Furthermore, we established a method for the simultaneous determination of ascorbate and dehydroascorbate in biological samples. By using this method, we investigated the effect of cyanate on the ascorbate- dehydroascorbate redox cycle in vivo. Consequently, we found a fact that cyanate causes depletion of ascorbate in organisms under the oxidative stress. In general, the patients with uremia suffer from the anemia caused by the deficiency of erythropoietin, which is synthesized by interstitial cells in kidney. Erythrocytes play a significant role in the detoxication of oxidative substances, so that the decrease of erythrocytes is responsible for the oxidative stress. These facts suggest that cyanate produced from urea decreased the ascorbate level in vivo through the mechanism described above.Ascorbate is an essential element for the collagen synthesis by connective tissue cells. The ascorbate deficiency is a possible factor for the construction of the fragile connective tissues in patients with uremia.