郑敬民,陈德君,尹广,赵文紧,李丽娟,王建平.C3aR过度活化与糖尿病肾病肾组织损伤的关系*[J].生物化学与生物物理进展(待发表)
C3aR过度活化与糖尿病肾病肾组织损伤的关系*
Roles of excessive C3aR signaling in the kidney damage of patients with diabetic nephropathy
投稿时间:2017-06-12  修订日期:2018-04-19
中文关键词:  C3a  C3aR  糖尿病肾病  足细胞  表达  病理意义
英文关键词:C3a, C3aR, diabetic  nephropathy, podocyte, expression, pathological  significance
基金项目:国家自然科学基金(81370828)
作者单位E-mail
郑敬民 南京军区南京总医院 国家肾脏疾病临床医学研究中心全军肾脏病研究所南京21002 zzjjmm7713@sina.com 
陈德君 恩泽医疗中心浙江省台州医院临海市 317000  
尹广 南京军区南京总医院 国家肾脏疾病临床医学研究中心全军肾脏病研究所南京21002  
赵文紧 南京军区南京总医院 国家肾脏疾病临床医学研究中心全军肾脏病研究所南京21002  
李丽娟 南京军区南京总医院 国家肾脏疾病临床医学研究中心全军肾脏病研究所南京21002  
王建平 南京军区南京总医院 国家肾脏疾病临床医学研究中心全军肾脏病研究所南京21002  
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中文摘要:
      C3aR是补体C3裂解产物C3a的受体.最近的一些研究提示C3aR通路可能参与了糖尿病肾病(DN)的病理过程,但有关C3aR通路在DN中的确切病理作用及有关机制远未清楚.需要特别指出的是,现有的有关C3aR参与DN肾组织损伤的证据主要来自一些动物模型的研究,临床上尚缺乏较为系统全面的对DN患者肾组织C3aR通路与肾组织损伤关系的观察分析.为此,本文首次以较大的样本量分析了不同病理时期DN患者肾组织C3aR和C3a的表达变化情况及其与DN患者肾组织损伤的相关性.在此基础上,进而利用体外细胞模型,对高糖环境下C3aR活化致肾小球足细胞损伤的作用及机制进行了探讨.结果显示:1)与正常对照相比,DN患者肾组织C3a和C3aR的表达水平随DN的进展而升高;C3aR在DN患者肾组织中的表达上调主要见于肾小管上皮细胞和肾小球足细胞.2)DN患者肾组织C3aR和C3a水平与患者肾组织损伤程度,特别是小管和小管间质损伤程度、肾小球足细胞损伤程度具有显著相关性.3)外加C3a激活C3aR可使高糖环境中的足细胞的细胞骨架发生明显改变、足细胞标记分子表达下调、足细胞通透性增加.这些结果说明:1)DN患者肾组织中确实存在C3a/C3aR轴过度活化的现象;2) C3a/C3aR轴的过度活化很可能在DN患者肾组织损伤,特别是小管和小管间质损伤、肾小球足细胞损伤中具有重要作用;3)可能通过破坏成熟足细胞特有的细胞骨架,改变足细胞标记分子表达,增加足细胞的通透性,C3a/C3aR轴过度活化参与DN足细胞损伤过程.本文不仅为C3a/C3aR通路参与DN病理过程提供了新的必不可少的临床证据,也增加了对C3a/C3aR通路过度活化致DN患者肾组织损伤机制,特别是肾小球足细胞损伤机制的了解,这对于拓展对DN病理机制的认识,发展DN防治新思路,无疑都是有益的.
英文摘要:
      C3aR is the receptor for C3a. Emerging evidence suggested that C3aR signaling might be involved in the pathogenesis of diabetic nephropathy (DN), but the exact significance and the underlying mechanisms are unclear. In particular, most of the data thus far have been derived from experimental studies; no study has reported the association of renal C3aR activation with the development of DN in DN patients. By using renal biopsy specimen from patients at different pathological stages, the present study investigated the expression of C3a and C3aR in the renal tissue of DN patients and associated them with the development of the disease. To determine the effect of C3aR activation in podocytes in DN condition, podocytes cultured in medium with high glucose were treated with C3a and the influences of C3aR activation in podocyte cytoskeleton, the expression of synaptopodin and alpha smooth muscle actin, and the permeability of podocyte monolayer were examined. Compared with the normal controls, renal expression of C3aR and C3a increased with the development of DN. C3aR was distributed mainly in tubular epithelial cells and glomerular podocytes. C3aR level in tubules and glomerulus was closely associated with the degree of tubular and glomerular damage, respectively. Activation of C3aR in podocytes induced re-organization of the cytoskeleton, down-regulation of synaptopodin, and increased permeability of the podocyte monolayer. The results indicted that a situation of excessive signaling through C3aR is present in the kidney of DN patients, which might contribute to the progression of DN. In particular, probably through destroying the podocyte characteristic cytoskeleton structure, decreasing the expression of podocyte specific molecules, and increasing the permeability of podocyte, excessive C3aR signaling contributes to the damage of glomerular podocytes.
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