J Clin Invest. 2014 Mar;124(3):1098-113. doi: 10.1172/JCI69778. Epub 2014 Feb 17.
Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α3 or β1 integrin, or the α3β1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in β1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.
足细胞是一种特化的富含肌动蛋白的上皮细胞，排列在肾脏肾小球滤过屏障的表面。足细胞与肾小球基底膜之间的连接需要整合素，α3 或β1 整合素或其配体层粘连蛋白的缺陷会导致小鼠模型发生肾病综合征。大型细胞骨架蛋白 talin1 不仅对整合素的激活至关重要，还直接将整合素与肌动蛋白细胞骨架连接起来。在这里，我们发现特异性缺失足细胞中 talin1 的小鼠表现出严重的蛋白尿、足突融合和肾功能衰竭。足细胞中 talin1 的缺失仅导致β1 整合素激活、足细胞黏附和细胞铺展适度减少；然而，talin1 的缺失会使足细胞的肌动蛋白细胞骨架发生深刻改变。对肾小球损伤的小鼠模型和肾病综合征患者的评估表明，足细胞中钙蛋白酶诱导的 talin1 裂解可能促进了肾病综合征的发病机制。此外，肾小球损伤后钙蛋白酶活性的药物抑制显著减少了 talin1 的裂解、白蛋白尿和足突融合。总之，这些发现表明足细胞中的 talin1 对于维持肾小球滤过屏障的完整性至关重要，并为肾病综合征的发病机制提供了新的认识。
