Podocytes are actin-rich epithelial cells whose effacement and detachment are the main cause of glomerular disease. Crk family proteins: Crk1/2 and CrkL are reported to be important intracellular signaling proteins that are involved in many biological processes. However, the roles of them in maintaining podocyte morphology and function remain poorly understood. In this study, specific knocking down of Crk1/2 and CrkL in podocytes caused abnormal cell morphology, actin cytoskeleton rearrangement and dysfunction in cell adhesion, spreading, migration, and viability. The p130Cas, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, p38 and JNK signaling pathways involved in these alterations. Furthermore, knocking down CrkL alone conferred a more modest phenotype than did the Crk1/2 knockdown and the double knockdown. Kidney biopsy specimens from patients with focal segmental glomerulosclerosis and minimal change nephropathy showed downregulation of Crk1/2 and CrkL in glomeruli. In zebrafish embryos, Crk1/2 and CrkL knockdown compromised the morphology and caused abnormal glomerular development. Thus, our results suggest that Crk1/2 and CrkL expression are important in podocytes; loss of either will cause podocyte dysfunction, leading to foot process effacement and podocyte detachment.

足细胞是富含肌动蛋白的上皮细胞，其脱落和脱落是肾小球疾病的主要原因。Crk家族蛋白：据报道Crk1 / 2和CrkL是重要的细胞内信号转导蛋白，涉及许多生物学过程。然而，它们在维持足细胞形态和功能中的作用仍知之甚少。在这项研究中，特异性敲低足细胞中的Crk1 / 2和CrkL会导致异常的细胞形态，肌动蛋白细胞骨架重排以及细胞黏附，扩散，迁移和生存能力障碍。p130Cas，粘着斑激酶，磷脂酰肌醇3-激酶/ Akt，p38和JNK信号通路参与了这些改变。此外，与Crk1 / 2敲除和双重敲除相比，单独敲除CrkL所赋予的表型更为温和。局灶性节段性肾小球硬化症和微小改变性肾病患者的肾脏活检标本显示肾小球中Crk1 / 2和CrkL的下调。在斑马鱼的胚胎中，Crk1 / 2和CrkL敲低损害了形态并引起了异常的肾小球发育。因此，我们的结果表明Crk1 / 2和CrkL在足细胞中的表达很重要。任一种的缺失都会引起足细胞功能障碍，导致足突消失和足细胞脱离。