Daniel T O, Stein E, Cerretti D P, St John P L, Robert B, Abrahamson D R
Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Kidney Int Suppl. 1996 Dec;57:S73-81.
Eph family receptor tyrosine kinases direct neuronal cell targeting, bundling and intercellular aggregation activity, yet their role in mammalian kidney development has been unexplored to date. We recently identified expression of ELK (Eph-like kinase) receptors in cultured human renal microvascular endothelial cells (HRMEC), and showed that ELK mediates their in vitro assembly into capillary-like structures in response to the exogenous ligand, LERK-2. Here we identify expression of the ELK ligand, LERK-2, in HRMEC and in primitive vascular structures of developing murine kidney. ELK and LERK-2 are expressed on endothelial progenitor cells of primitive microvasculature in a pattern similar to that of the VEGF receptor, flk-1. ELK LERK-2 and flk-1 antigens are also displayed on the branching ureteric bud epithelium; ELK and LERK-2 expression persists in mature collecting ducts, glomeruli and arterioles. To explore whether renal-derived endothelial cells may distinguish LERK-2 from the angiogenic Eck ligand, LERK-1 (B61), and whether endothelial cells from different sources may distinguish among Eph receptor ligands, we compared HRMEC and human umbilical vein endothelial cell (HUVEC) responses in an in vitro capillary-like assembly assay. HRMEC endothelial cells assembled capillary-like structures in response to LERK-2, but not LERK-1, under conditions that promoted HUVEC to assemble in response to LERK-1, but not LERK-2. Therefore, responses mediated through specific Eph family receptors (ELK and Eck) are discriminated by endothelial cells from different vascular bed sources. ELK and its ligand, LERK-2, are spatially and temporally coordinated in expression and may function in morphogenesis of the renal microvasculature.
Eph家族受体酪氨酸激酶指导神经元细胞靶向、成束及细胞间聚集活动，然而它们在哺乳动物肾脏发育中的作用迄今尚未得到探索。我们最近在培养的人肾微血管内皮细胞（HRMEC）中鉴定出ELK（Eph样激酶）受体的表达，并表明ELK介导它们在体外响应外源性配体LERK-2组装成毛细血管样结构。在此，我们鉴定出ELK配体LERK-2在HRMEC以及发育中小鼠肾脏的原始血管结构中的表达。ELK和LERK-2在原始微血管的内皮祖细胞上以与VEGF受体flk-1相似的模式表达。ELK、LERK-2和flk-1抗原也显示在分支的输尿管芽上皮上；ELK和LERK-2的表达在成熟的集合管、肾小球和小动脉中持续存在。为了探究肾源性内皮细胞是否能够区分LERK-2与血管生成性Eck配体LERK-1（B61），以及不同来源的内皮细胞是否能够区分Eph受体配体，我们在体外毛细血管样组装试验中比较了HRMEC和人脐静脉内皮细胞（HUVEC）的反应。在促进HUVEC响应LERK-1而非LERK-2组装的条件下，HRMEC内皮细胞响应LERK-2而非LERK-1组装成毛细血管样结构。因此，不同血管床来源的内皮细胞能够区分通过特定Eph家族受体（ELK和Eck）介导的反应。ELK及其配体LERK-2在表达上在空间和时间上是协调的，并且可能在肾微血管的形态发生中发挥作用。
