Dept. of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2):R340-8. doi: 10.1152/ajpregu.00640.2009. Epub 2010 Nov 3.
The slit diaphragm connecting the adjacent foot processes of glomerular epithelial cells (podocytes) is the final barrier of the glomerular capillary wall and serves to prevent proteinuria. Podocytes are understood to be terminally differentiated cells and share some common features with neurons. Neurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation. Although neurexin has been understood to be specifically expressed in neuronal tissues, we found that neurexin was expressed in several organs. Several forms of splice variants of neurexin-1α were detected in the cerebrum, but only one form of neurexin-1α was detected in glomeruli. Immunohistochemical study showed that neurexin restrictedly expressed in the podocytes in kidneys. Dual-labeling analyses showed that neurexin was colocalized with CD2AP, an intracellular component of the slit diaphragm. Immunoprecipitation assay using glomerular lysate showed that neurexin interacted with CD2AP and CASK. These observations indicated that neurexin localized at the slit diaphragm area. The staining intensity of neurexin in podocytes was clearly lowered, and their staining pattern shifted to a more discontinuous patchy pattern in the disease models showing severe proteinuria. The expression and localization of neurexin in these models altered more clearly and rapidly than that of other slit diaphragm components. We propose that neurexin is available as an early diagnostic marker to detect podocyte injury. Neurexin coincided with nephrin, a key molecule of the slit diaphragm detected in a presumptive podocyte of the developing glomeruli and in the glomeruli for which the slit diaphragm is repairing injury. These observations suggest that neurexin is involved in the formation of the slit diaphragm and the maintenance of its function.
相邻肾小球上皮细胞（足细胞）的足突之间的裂孔隔膜是肾小球毛细血管壁的最后一道屏障，可防止蛋白尿的产生。足细胞被认为是终末分化细胞，与神经元具有一些共同特征。神经连接蛋白是一种突触前黏附分子，在突触分化中起作用。尽管神经连接蛋白被理解为特异性表达于神经元组织中，但我们发现神经连接蛋白在几个器官中均有表达。在大脑中检测到神经连接蛋白 1α 的几种剪接变体形式，但在肾小球中仅检测到一种神经连接蛋白 1α 形式。免疫组织化学研究表明，神经连接蛋白在肾脏中的足细胞中特异性表达。双重标记分析表明，神经连接蛋白与 CD2AP（裂孔隔膜的一种细胞内成分）共定位。使用肾小球裂解物进行免疫沉淀分析表明，神经连接蛋白与 CD2AP 和 CASK 相互作用。这些观察结果表明神经连接蛋白定位于裂孔隔膜区域。在显示严重蛋白尿的疾病模型中，足细胞中的神经连接蛋白染色强度明显降低，其染色模式转变为更不连续的斑片状模式。在这些模型中，神经连接蛋白的表达和定位的改变比其他裂孔隔膜成分更为明显和迅速。我们提出，神经连接蛋白可作为一种早期诊断标志物，用于检测足细胞损伤。神经连接蛋白与裂孔隔膜的关键分子nephrin 同时存在，nephrin 存在于发育中的肾小球的假定足细胞中，也存在于修复裂孔隔膜损伤的肾小球中。这些观察结果表明，神经连接蛋白参与了裂孔隔膜的形成和功能的维持。
