Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (Yap) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.

中文翻译：

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抑制转录共激活因子 YAP 损害糖尿病足细胞损伤中转录因子 WT1 的表达和功能 

足细胞损伤和丢失是糖尿病肾病（DN）的标志。然而，这些现象背后的分子机制仍然知之甚少。 YAP（Yes 相关蛋白）是一种重要的转录共激活因子，可与多种其他转录因子结合，包括 TEAD 家族成员（Hippo 途径的核效应子），调节细胞增殖、分化和凋亡。本研究发现糖尿病小鼠和人肾脏足细胞中 YAP S127 的 YAP 磷酸化增加，核 YAP 定位减少，表明 YAP 失调可能在糖尿病足细胞损伤中发挥作用。他莫昔芬诱导的足细胞特异性 Yap 基因敲除小鼠 (Yap) 表现出加速和恶化的糖尿病肾损伤。 YAP 失活降低了转录因子 WT1 的表达，随后糖尿病足细胞中 WT1 和其他众所周知的靶标减少。因此，我们的研究不仅揭示了 Hippo 通路在糖尿病足细胞损伤中的病理生理学作用，而且还可能导致开发新的治疗策略，通过靶向 Hippo 信号通路来预防和/或治疗 DN。