Lahdenkari Anne-Tiina, Lounatmaa Kari, Patrakka Jaakko, Holmberg Christer, Wartiovaara Jorma, Kestilä Marjo, Koskimies Olli, Jalanko Hannu
Hospital for Children and Adolescents, University of Helsinki, 00290, Finland.
J Am Soc Nephrol. 2004 Oct;15(10):2611-8. doi: 10.1097/01.ASN.0000139478.03463.D9.
Glomerular epithelial cells (podocytes) play an important role in the pathogenesis of proteinuria. Podocyte foot process effacement is characteristic for proteinuric kidneys, and genetic defects in podocyte slit diaphragm proteins may cause nephrotic syndrome. In this work, a systematic electron microscopic analysis was performed of the structural changes of podocytes in two important nephrotic kidney diseases, congenital nephrotic syndrome of the Finnish type and minimal-change nephrotic syndrome (MCNS). The results showed that (1) podocyte foot process effacement was present not only in proteinuric glomeruli but also in nonproteinuric MCNS kidneys; (2) podocytes in proteinuric glomeruli did not show detachment from the basement membrane or cell membrane ruptures; (3) the number of pinocytic membrane invaginations in the basal and apical parts of the podocytes was comparable in proteinuric and control kidneys; (4) in proteinuric kidneys, the podocyte slit pore density was decreased by 69 to 80% and up to half of the slits were so "tight" that no visible space between foot processes was seen; thus, the filtration surface area between podocytes was dramatically reduced; and (5) in the narrow MCNS slit pores, nephrin was located in the apical part of the podocyte foot process, indicating vertical transfer of the slit diaphragm complex in proteinuria. In conclusion, these results suggest that protein leakage in the two nephrotic syndromes studied occurs through defective podocyte slits, and the other structural alterations commonly seen in electron microscopy are secondary to, not a prerequisite for, the development of proteinuria.
肾小球上皮细胞（足细胞）在蛋白尿的发病机制中起重要作用。足细胞足突消失是蛋白尿性肾脏的特征，足细胞裂孔隔膜蛋白的基因缺陷可能导致肾病综合征。在这项研究中，我们对两种重要的肾病性肾脏疾病——芬兰型先天性肾病综合征和微小病变肾病综合征（MCNS）中的足细胞结构变化进行了系统的电子显微镜分析。结果显示：（1）足细胞足突消失不仅存在于蛋白尿性肾小球中，也存在于非蛋白尿性的MCNS肾脏中；（2）蛋白尿性肾小球中的足细胞未显示从基底膜脱离或细胞膜破裂；（3）蛋白尿性肾脏和对照肾脏中足细胞基底和顶端部分的胞饮膜内陷数量相当；（4）在蛋白尿性肾脏中，足细胞裂孔密度降低了69%至80%，高达一半的裂孔非常“紧密”，以至于在足突之间看不到可见的间隙；因此，足细胞之间的滤过表面积显著减少；（5）在狭窄的MCNS裂孔中，nephrin位于足细胞足突的顶端部分，表明裂孔隔膜复合物在蛋白尿中发生了垂直转移。总之，这些结果表明，在所研究的两种肾病综合征中，蛋白质渗漏是通过有缺陷的足细胞裂孔发生的，而电子显微镜下常见的其他结构改变是蛋白尿发展的继发结果，而非先决条件。
