Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and α3 integrin
Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and α3 integrin
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DOI：
10.1074/jbc.m401973200
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发表时间：
2004-08-13
影响因子：
4.8
通讯作者：
Mundel, P
中科院分区：
文献类型：
--
作者：
Reiser, J;Oh, J;Mundel, P
足细胞足突消失和裂隙隔膜破坏通常与肾小球蛋白尿有关，并且可以通过注射嘌呤霉素氨基核苷在大鼠中诱导。在这里，我们发现嘌呤霉素氨基核苷肾病的诱导涉及足细胞迁移，这是通过半胱氨酸蛋白酶组织蛋白酶 L 和 α(3) 整联蛋白之间的协调相互作用进行的。嘌呤霉素氨基核苷处理可上调体内足细胞中组织蛋白酶 L 的表达以及体外足细胞中组织蛋白酶 L 的表达和酶活性。来自缺乏组织蛋白酶 L 的小鼠的分离足细胞受到保护，免受细胞嘌呤霉素氨基核苷诱导的细胞分离。通过观察到嘌呤霉素氨基核苷诱导的细胞迁移在组织蛋白酶 L 缺陷的足细胞中减慢，以及细胞与细胞接触的保存和重要裂隙隔膜蛋白 CD2AP 的表达，强调了组织蛋白酶 L 表达的功能意义。在缺乏 α(3) 整合素的足细胞中诱导组织蛋白酶 L 表达和活性。类似地，用阻断抗体对野生型足细胞中的α(3)整合素进行急性功能性抑制可增加组织蛋白酶L活性的表达。 α(3) 整合素的下调可防止嘌呤霉素氨基核苷诱导的足细胞脱离。总之，这些数据证实足细胞足突消失是一种迁移事件，涉及组织蛋白酶 L 和 α(3) 整合素之间的新型相互作用。
Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and alpha(3) integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute functional inhibition of alpha(3) integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Downregulation of alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and alpha(3) integrin.