Research on The Mechanisms of Tubulointerstitial Injury by Proteinuria.

由于肾小管间质损伤与蛋白尿密切相关，两者都是较好的预测肾损伤预后的指标，本项目旨在探讨与蛋白尿相关的肾小管间质损伤的机制。在本研究中，补体存在于肾病患者的肾小管液的作用进行了研究。第一部分以氨基核苷致肾病大鼠为实验对象，第7天观察到明显的肾小管间质损伤和补体沉积，结果如下：(1)眼镜蛇毒因子（CVF）对血清补体的消耗不影响蛋白尿，但可显著减少补体在小管中的沉积和小管间质损伤；(2)可溶性CR1是补体激活的C3水平抑制剂，与CVF具有相同的作用。第二部分测定各种肾小球疾病患者的补体激活产物（CAP，即C3水平的iC3b和Bb， C9水平的MAC）。所得结果如下：(1)尿中CAP的排泄量与蛋白尿量呈正相关，(2)蛋白尿患者、局灶性肾小球硬化患者和糖尿病肾病患者尿中CAP的量显著升高，(3)膜性肾病患者尿中MAC的排泄量升高，而iC3b和Bb未升高，(4)肾功能不全患者，碳酸氢钠纠正酸中毒可显著减少尿中CAP的排泄，但不影响血清CAP水平和尿蛋白排泄。这些结果表明，在蛋白尿的情况下，尿液中的补体成分在小管腔中被激活并损伤小管细胞，从而促进小管间质损伤。

The aim of this project was to investigate the mechanisms of tubulointerstitial injury associated with proteinuria, since tubulointerstitial injury and proteinuria are closely related with each other and both of them are the better predictors for prognosis of renal injury. In the present study, the role of complement present in the tubular fluid of nephrotic subjects was investigated. In the first part of experiment using rats made nephrotic by aminonucleoside in which significant tubulointerstitial injury and tubular deposition of complement were observed at 7 days, the following results were obtained. (1) Depletion of serum complement by cobra venom factor (CVF) did not affect proteinuria, but significantly reduced deposition of complement in the tubules and tubulointerstitial injury, (2) soluble CR1, an inhibitor of complement activation at C3 level, had the same effects as CVF.In the second part, complement activation products (CAP, i.e., iC3b and Bb at C3 level, and MAC at C9 level) were measured in the patients with various glomerular diseases. The results *otained were as follow ; (1) Urinary excretion of CAP was positively correlated with the amount of proteinuria, (2) among proteinuric patients, those with focal glomerular sclerosis and diabetic nephropathy showed significantly elevated amount of CAP in the urine, (3) in case of membranous nephropathy, urinary excretion of MAC was increased, whereas iC3b and Bb were not increased, (4) in the patients with renal insufficiency, correction of acidosis by sodium bicarbonate significantly reduced urinary excretion of CAP without affecting the serum level of CAP and urinary protein excretion. These results indicate that, in the proteinuric condition, complement components present in the urine are activated in the tubular lumen and injure the tubular cells resulting in the promotion of tubulointerstitial injury.