Blattner Simone Monika, Kretzler Matthias
Nephrology Center, University of Munich, Munich, Germany.
Curr Opin Nephrol Hypertens. 2005 Jul;14(4):404-10. doi: 10.1097/01.mnh.0000172730.67746.5b.
Cellular functions like proliferation, differentiation, migration, morphogenesis and apoptosis are modulated by the extracellular matrix. Integrins are the prototypic heterodimeric transmembrane matrix receptors with competing affinities for individual extracellular matrix ligands. The intracellular integrin domain clusters cytoplasmic proteins into focal adhesion plaques for bidirectional (outside-in and inside-out) signalling. Integrin-linked kinase organizes the connections of the extracellular matrix via integrins to the cytoskeleton and is involved in adhesion plaque signalling. In this review, an introduction of integrin-linked kinase structure and function is followed by a summary of our current understanding of integrin-linked kinase in renal disease with special focus on glomerular cell-matrix interaction.
Differential regulation of integrin-linked kinase has been observed during the pathogenesis of glomerular disease and tubulo-interstitial fibrosis. In outside-in signalling integrin-linked kinase mediates the response of renal cells to alterations in matrix and growth factor environments. Inside-out signalling transduces inflammatory and oxidative stress responses into decreased matrix attachment. Downstream signalling of integrin-linked kinase activates the Wnt pathway with a switch towards a proliferative, mesenchymal phenotype. In concert with interacting molecules integrin-linked kinase influences the actin cytoskeleton, resulting in shape change and focal adhesion dysfunction observed in podocyte failure and tubulo-interstitial fibrosis.
Integrin-linked kinase has emerged as a key player at the interface between extracellular matrix, integrins, actin-based cytoskeleton and cellular phenotype in kidney diseases. Future studies focusing on interacting molecules and modification of integrin-linked kinase function in vivo will better define the role of cell matrix signalling in progressive renal failure.
细胞功能如增殖、分化、迁移、形态发生和凋亡受细胞外基质调节。整合素是典型的异二聚体跨膜基质受体，对单个细胞外基质配体具有竞争性亲和力。整合素的细胞内结构域将细胞质蛋白聚集到粘着斑中，用于双向（外向内和内向内）信号传导。整合素连接激酶通过整合素组织细胞外基质与细胞骨架的连接，并参与粘着斑信号传导。在本综述中，先介绍整合素连接激酶的结构和功能，然后总结我们目前对整合素连接激酶在肾脏疾病中的认识，特别关注肾小球细胞-基质相互作用。
在肾小球疾病和肾小管间质纤维化的发病机制中观察到整合素连接激酶的差异调节。在外向内信号传导中，整合素连接激酶介导肾细胞对基质和生长因子环境改变的反应。内向内信号传导将炎症和氧化应激反应转化为基质附着减少。整合素连接激酶的下游信号激活Wnt通路，向增殖性间充质表型转变。与相互作用分子协同作用，整合素连接激酶影响肌动蛋白细胞骨架，导致足细胞功能障碍和肾小管间质纤维化中观察到的形状改变和粘着斑功能障碍。
整合素连接激酶已成为肾脏疾病中细胞外基质、整合素、基于肌动蛋白的细胞骨架和细胞表型之间界面的关键参与者。未来聚焦于体内相互作用分子和整合素连接激酶功能修饰的研究将更好地定义细胞基质信号在进行性肾衰竭中的作用。
