Integrin linked kinase as a candidate downstream effector in proteinuria
Integrin linked kinase as a candidate downstream effector in proteinuria
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DOI：
10.1096/fj.00-0832fje
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发表时间：
2001-06-01
期刊：
影响因子：
4.8
通讯作者：
Holthöfer, H
中科院分区：
文献类型：
--
作者：
Kretzler, M;Teixeira, VPC;Holthöfer, H
肾小球负责产生无蛋白质的超滤液。损伤后，它表现出特征性的一致反应，导致进行性肾衰竭。遗传性蛋白尿疾病的最新研究揭示了参与足细胞-细胞和细胞-基质相互作用的分子的突变。蛋白尿中激活的相关细胞信号传导事件迄今尚未分析。为了鉴定蛋白尿诱导的分子，我们使用芬兰型先天性肾病综合征患儿肾小球mRNA差异显示。确定了整合素连接激酶（ILK）mRNA（β（1）-整合素偶联丝氨酸苏氨酸激酶）的增加。观察表明ILK在肾小球衰竭中的作用。在两种蛋白尿小鼠模型中发现肾小球和单个足细胞ILK mRNA的上调。在培养的足细胞中，整合素附着于基质抑制ILK活性和嘌呤霉素激活的ILK对足细胞的损伤。ILK在小鼠足细胞中的稳定过表达引起基质粘附减少，并导致相当大的表型改变相比，激酶缺陷型ILK的表达，平行方面的体内足细胞损伤。这些结果与ILK作为足细胞基质相互作用的协调中的相关参与者和肾小球疾病中足细胞渗透选择性的候选下游调节剂一致。
The kidney glomerulus is responsible for the generation of a protein-free ultrafiltrate. After injury, it shows a characteristic, uniform response leading to progressive renal failure. Recent studies of hereditary proteinuric diseases have revealed mutations in molecules involved in podocyte cell-cell and cell-matrix interaction. Associated cellular signaling events activated in proteinuria have not been analyzed so far. To identify proteinuria-induced molecules, we used mRNA differential display in glomeruli from children with congenital nephrotic syndrome of the Finnish type. An increase in integrin linked kinase (ILK) mRNA, beta (1)-integrin coupled serine threonine kinase, was identified. Observations suggest a role for ILK in glomerular failure. An up-regulation of glomerular and Single-podocyte ILK mRNA was found in two murine models of proteinuria. In cultured podocytes, integrin attachment to matrix inhibited ILK activity and podocyte damage with puromycin activated ILK. Stable overexpression of ILK in murine podocytes caused reduced matrix adhesion and led to considerable phenotype alteration compared with expression of a kinase-defective ILK, paralleling aspects of in vivo podocyte damage. These results are consistent with ILK as a relevant player in the orchestration of podocyte matrix interaction and a candidate downstream regulator of podocyte permselectivity in glomerular diseases.