Tubulointerstitial heparan sulfate proteoglycan changes in human renal diseases correlate with leukocyte influx and proteinuria
Tubulointerstitial heparan sulfate proteoglycan changes in human renal diseases correlate with leukocyte influx and proteinuria
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DOI：
10.1152/ajprenal.00429.2007
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发表时间：
2008-01-01
影响因子：
4.2
通讯作者：
van den Born, J.
中科院分区：
文献类型：
--
作者：
Celie, J. W. A. M.;Reijmers, R. M.;van den Born, J.
硫酸乙酰肝素蛋白多糖(HSPGs)因其在肾小球滤过中的作用而广为人知。此外，HSPGs还能与白细胞黏附分子L-选择素和趋化因子结合，提示其在炎症中的作用。我们研究了代表不同人类原发肾脏疾病的一组活检组织中L-选择素和单核细胞趋化蛋白-1的结合。在各种肾脏疾病中，L-选择素和单核细胞趋化蛋白-1与间质血管周围基质热休克蛋白结合增加，与白细胞内流显著相关。在蛋白尿疾病中，包括膜性肾小球疾病、微小病变病，但也包括IgA肾病和狼疮性肾炎，观察到L-选择素和单核细胞趋化蛋白-1与肾小管上皮细胞(TEC)HSPGs结合增加，这与基础侧Syndecan-1和抗硫酸乙酰肝素10E4染色增加共存。短发夹状RNA介导的沉默表明TECs上的Syndecan-1确实介导了L-选择素的结合。蛋白尿症患者活检组织中IL-8的表达增加，提示腔蛋白的增加可能激活了血管内皮细胞，使L-选择素和单核细胞趋化蛋白-1结合Syndecan-1的表达增加。值得注意的是，与健康对照组相比，蛋白尿症患者的尿液Syndecan-1与L-选择素的结合能力较差，尽管两组的Syndecan-1浓度相似。总之，我们的数据显示，在原发性肾脏疾病中，肾小管间质HSPG发生了明显的改变，这可能会影响炎症反应。
Heparan sulfate proteoglycans (HSPGs) are well known for their proposed role in glomerular filtration. In addition, HSPGs can bind the leukocyte adhesion molecule L-selectin and chemokines, suggesting a role in inflammation. We examined a panel of biopsies representing different human primary kidney diseases for L-selectin and monocyte chemoattractant protein-1 (MCP-1) binding. In various renal diseases, L-selectin and MCP-1 binding to interstitial perivascular matrix HSPGs is increased, which is significantly associated with leukocyte influx. In proteinuric diseases, including membranous glomerulopathy, minimal change disease, but also IgA nephropathy and lupus nephritis, increased binding of L-selectin and MCP-1 to tubular epithelial cell (TEC) HSPGs is observed, which colocalizes with increased basolateral syndecan-1 and anti-heparan sulfate 10E4 staining. Short-hairpin RNA-mediated silencing demonstrates that syndecan-1 on TECs indeed mediates L-Selectin binding. Increased TEC expression of IL-8 in biopsies of proteinuric patients suggests that the increase in luminal protein may activate TECs to increase expression of L-selectin and MCP-1 binding syndecan-1. Strikingly, urinary syndecan-1 from proteinuric patients is less capable of binding L-selectin compared with urinary syndecan-1 from healthy controls, although syndecan-1 concentrations are similar in both groups. Together, our data show pronounced tubulointerstitial HSPG alterations in primary kidney disease, which may affect the inflammatory response.