Research on The Mechanisms of Tubulointerstitial Injury by Proteinuria.

本课题的目的是探讨肾小管间质损伤与蛋白尿相关的机制，因为肾小管间质损伤与蛋白尿密切相关，两者都是预测肾损伤预后的较好指标。在本研究中，我们研究了肾病患者肾小管液中补体的作用。在实验的第一部分，用氨基核苷制作的大鼠肾病模型，在第7天观察到明显的肾小管间质损伤和补体在肾小管的沉积。(1)眼镜蛇毒因子(CVF)耗竭血清补体不影响蛋白尿，但显著减少补体在肾小管和肾小管间质的沉积；(2)C3水平补体激活抑制物可溶性CR1的作用与CVF相同。第二部分，检测不同肾小球疾病患者补体激活产物(CAP，即C3水平的补体活化产物IC3b、BB和C9水平的MAC)。结果表明：(1)尿CAP排泄量与蛋白尿量呈正相关；(2)在蛋白尿症患者中，局灶性肾小球硬化和糖尿病肾病患者尿CAP明显升高；(3)膜性肾病患者尿MAC增加，而iC3b和BB无明显增加；(4)肾功能不全患者，碳酸氢钠纠正酸中毒后，CAP尿排泄量明显减少，对血清CAP水平和尿蛋白排泄量无明显影响。这些结果表明，在蛋白尿条件下，尿液中的补体成分在肾小管腔内被激活，并损伤肾小管细胞，从而促进肾小管间质损伤。

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.