Research on The Role of Complement Regulatory Membrane Factors in The Initiation and Progression of Glomerular Injury

本项目旨在阐明补体调节膜因子（CRMFs）在肾小球损伤发病机制中的体内作用。crmf在两个层面起作用，即C3扩增水平和膜攻击复合物（MAC）的形成水平。以下是本研究项目的新发现。(1)在人和大鼠中，CRMFs在包括肾小球在内的正常肾脏和其他器官中均有显著表达。(2)通过中和单克隆抗体在体内系统性抑制这些因子的功能，导致大鼠出现内毒素休克样症状。这一发现首次证明了CRMFs在保护宿主器官免受自发发生的补体攻击方面起着至关重要的作用。(3)利用本实验室研制的离体肾灌注系统，在大鼠肾脏中实现了CRMFs的选择性抑制。当补体依赖性肾小球损伤在crmf抑制的大鼠中引起时，补体激活产物的沉积增加，肾小球损伤明显增强。这些发现首次在体内证实肾小球内的CRMFs在这类肾小球损伤的发病机制中起保护作用。本研究项目还获得了以下关于CRMFs在小管间质损伤发病机制中的作用的初步发现。(1)在没有补体激活刺激的情况下，功能性抑制小管间质CRMF导致小管间质病变的发生。因此，crmf对于维持肾脏的正常完整性非常重要。(2)小管周围毛细血管中CRMFs的功能抑制导致血浆蛋白通透性增加，并导致小管间质损伤。因此，推进这一领域的研究将有助于进一步认识进行性肾损伤的机制。少

This project was performed to elusidate the in vivo role of complement regulatory membrane factors (CRMFs) in the pathegenesis of glomerular injury. CRMFs work at two levels, i. e., the level of C3 amplification and the level of formation of membrane attack complex (MAC). The following new findings were obtained from this research project. (1) Both in human and rats, CRMFs were significantly expressed in the normal kidney including glomeruli, and in other organs. (2) Systemic suppression of the function of these factors in vivo by neutralizing monoclonal antibodies result in the endotoxin shock-like symptoms in rats. It was demonstrated for the first time by this finding that CRMFs play crucial roles for the protection of host organs from the spontaneously occurring complement attack. (3) Using an isolated kidney perfusion system developed in our laboratory, selective suppression of CRMFs in the kidney was achieved in rats. When complement-dependent glomerular injury was induced in the … More se CRMF-suppressed rats, glomerular injury was significantly enhanced with increased deposition of complement activation products. From these findings, it was testified in vivo for the first time that CRMFs in the glomeruli play protective roles in the pathogenesis of this kind of glomerular injury.The following preliminary findings concerning the role of CRMFs in the pathogenesis of tubulointerstitial injury were also obtained by the present research project. (1) Functional suppression of tubulointerstitial CRMF resulted in the development of tubulointerstitial lesion without any complement-activating stimuli. Thus, CRMFs are important for maintaining the normal integrity of the kidney. (2) Functional suppression of CRMFs in the peritubular capillaries resulted in the increased permeability for plasma proteins, and in the tubulointerstitial injury. It is concluded that promotion of the research in this field must greatly contribute to the understanding of the mechanisms of progressive renal injury. Less