Expression of ILK in renal stroma is essential for multiple aspects of renal development
Expression of ILK in renal stroma is essential for multiple aspects of renal development
复制标题
ILK 在肾基质中的表达对于肾脏发育的多个方面至关重要
DOI：
10.1152/ajprenal.00509.2017
复制
发表时间：
2018-08-01
影响因子：
4.2
通讯作者：
Liang, Xingqun
中科院分区：
文献类型：
--
作者：
Gong, Xiaohui;Guo, Xiaoxia;Liang, Xingqun
肾脏发育包括输尿管芽(UB)和周围的后肾间充质之间的相互和诱导的相互作用。肾间质来源的信号对于肾上皮细胞和间充质细胞类型的分化和模式形成以及肾血管生成是必不可少的；然而，其潜在的机制仍不完全清楚。整合素连接蛋白激酶(ILK)是整合素信号通路的重要组成部分，在肾脏发育过程中发挥着重要作用。然而，ILK在肾间质中的作用仍不清楚。在这里，我们使用血小板衍生生长因子受体B(PDGFRb)-Cre小鼠品系来去除肾基质系中的ILK，结果导致ILK突变小鼠出现出生后生长迟缓，并在出生后3周内死亡，并伴有严重的肾脏发育缺陷。PDGFRb-Cre；ILK突变肾脏UB分支明显减少，集合管形成中断。从胚胎16.5开始，肾间质变得紊乱。形成髓质间质假性囊肿。PDGFRb-Cre；ilk突变体表现为肾血管构型错误和肾小球血管分化受损。在PDGFRb-Cre；ILK突变肾脏中观察到胶质细胞源性神经营养因子/Ret和骨形态发生蛋白7信号通路受损。此外，磷酸化蛋白质组学和Western印迹分析显示，在PDGFRb-Cre；ilk突变体中，肾脏形态发生所需的一些关键信号通路存在显著的失调，包括PI3K/AKT和MAPK/ERK。我们的结果揭示了ILK在肾间质和血管发育中的关键需求，以及ILK在UB分支形态发生中的非细胞自主作用。
Kidney development involves reciprocal and inductive interactions between the ureteric bud (UB) and surrounding metanephric mesenchyme. Signals from renal stromal lineages are essential for differentiation and patterning of renal epithelial and mesenchymal cell types and renal vasculogenesis; however, underlying mechanisms remain not fully understood. Integrin-linked kinase (ILK), a key component of integrin signaling pathway, plays an important role in kidney development. However, the role of ILK in renal stroma remains unknown. Here, we ablated ILK in renal stromal lineages using a platelet-derived growth factor receptor B (Pdgfrb)-Cre mouse line, and the resulting Ilk mutant mice presented postnatal growth retardation and died within 3 wk of age with severe renal developmental defects. Pdgfrb-Cre;Ilk mutant kidneys exhibited a significant decrease in UB branching and disrupted collecting duct formation. From E16.5 onward, renal interstitium was disorganized. forming medullary interstitial pseudocysts. Pdgfrb-Cre;Ilk mutants exhibited renal vasculature mispatterning and impaired glomerular vascular differentiation. Impaired glial cell-derived neurotrophic factor/Ret and bone morphogenetic protein 7 signaling pathways were observed in Pdgfrb-Cre;Ilk mutant kidneys. Furthermore, phosphoproteomic and Western blot analyses revealed a significant dysregulation of a number of key signaling pathways required for kidney morphogenesis, including PI3K/AKT and MAPK/ERK in Pdgfrb-Cre;Ilk mutants. Our results revealed a critical requirement for ILK in renal-stromal and vascular development, as well as a nonceil autonomous role of ILK in UB branching morphogenesis.