Podocyte injury is an important cause of proteinuria. Angiopoietin-like protein 4 (Angptl4) is a secreted glycoprotein and has a role in proteinuria. However, the exact role of Angptl4 in podocyte injury and its upstream regulators has not been clarified. In this study, we used lipopolysaccharide (LPS)-induced mice and cultured podocytes as podocyte injury models. Our results indicated that LPS increased the expression of podocyte Angptl4 in vivo and in vitro. Furthermore, we showed that Angptl4 overexpression deteriorated LPS-induced podocyte injury by inducing podocyte cytoskeleton rearrangement, reducing the expression of synaptopodin while Angptl4 knockdown alleviated LPS-induced podocyte injury. In addition, we found that inhibitors and siRNA targeting TLR4/MyD88/NF-κB signaling inhibited the upregulation of Angptl4 in LPS-induced podocytes. Moreover, inhibitors and siRNA targeting calcineurin/NFAT signaling also relieved LPS-induced Angptl4 expression and podocyte injury in vivo and in vitro. Taken together, our study has elucidated that both of the TLR4/MyD88/NF-κB and calcineurin/NFAT signaling mediate the upregulation of Angptl4 in LPS-induced podocytes, which has important implications for further understanding the molecular mechanism of LPS-induced podocyte injury.

足细胞损伤是蛋白尿的重要原因。血管生成素样蛋白 4 (Angptl4) 是一种分泌型糖蛋白，在蛋白尿中起作用。然而，Angptl4 在足细胞损伤及其上游调节剂中的确切作用尚未阐明。在这项研究中，我们使用脂多糖（LPS）诱导的小鼠和培养的足细胞作为足细胞损伤模型。我们的结果表明LPS在体内和体外增加足细胞Angptl4的表达. 此外，我们发现 Angptl4 过表达通过诱导足细胞细胞骨架重排，降低突触足蛋白的表达，而 Angptl4 敲低减轻 LPS 诱导的足细胞损伤，从而恶化了 LPS 诱导的足细胞损伤。此外，我们发现靶向 TLR4/MyD88/NF-κB 信号传导的抑制剂和 siRNA 抑制了 LPS 诱导的足细胞中 Angptl4 的上调。此外，靶向钙调神经磷酸酶/NFAT 信号的抑制剂和 siRNA在体内和体外也减轻了 LPS 诱导的 Angptl4 表达和足细胞损伤. 综上所述，我们的研究阐明了 TLR4/MyD88/NF-κB 和 calcineurin/NFAT 信号介导 LPS 诱导的足细胞中 Angptl4 的上调，这对于进一步了解 LPS 诱导的足细胞损伤的分子机制具有重要意义。 .