Podocyte loss triggering aberrant activation and proliferation of parietal epithelial cells (PECs) is a central pathogenic event in proliferative glomerulopathies. Podocyte-specific Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, is essential for maintaining podocyte homeostasis and PEC quiescence. Using mice with podocyte-specific knockdown of Klf4, we conducted glomerular RNA-sequencing, tandem mass spectrometry, and single-nucleus RNA-sequencing to identify cell-specific transcriptional changes that trigger PEC activation due to podocyte loss. Integration with in silico chromatin immunoprecipitation identified key ligand-receptor interactions, such as fibronectin 1 (FN1)–αVβ6, between podocytes and PECs dependent on KLF4 and downstream signal transducer and activator of transcription 3 (STAT3) signaling. Knockdown of Itgb6 in PECs attenuated PEC activation. Additionally, podocyte-specific induction of human KLF4 or pharmacological inhibition of downstream STAT3 activation reduced FN1 and integrin β 6 (ITGB6) expression and mitigated podocyte loss and PEC activation in mice. Targeting podocyte-PEC crosstalk might be a critical therapeutic strategy in proliferative glomerulopathies.

中文翻译：

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足细胞特异性 KLF4 是维持肾脏壁上皮细胞静止所必需的

足细胞丢失引发壁上皮细胞（PEC）的异常激活和增殖是增殖性肾小球病的核心致病事件。足细胞特异性 Krüppel 样因子 4 (KLF4) 是一种锌指转录因子，对于维持足细胞稳态和 PEC 静止至关重要。使用足细胞特异性敲低 Klf4 的小鼠，我们进行了肾小球 RNA 测序、串联质谱分析和单核 RNA 测序，以鉴定由于足细胞丢失而触发 PEC 激活的细胞特异性转录变化。与计算机染色质免疫沉淀的整合确定了足细胞和 PEC 之间依赖 KLF4 和下游信号转导器和转录激活剂 3 (STAT3) 信号传导的关键配体 - 受体相互作用，例如纤连蛋白 1 (FN1)-αVβ6。PEC 中 Itgb6 的敲低减弱了 PEC 的激活。此外，足细胞特异性诱导人 KLF4 或下游 STAT3 激活的药理抑制可减少 FN1 和整合素 β 6 (ITGB6) 的表达，并减轻小鼠足细胞损失和 PEC 激活。靶向足细胞-PEC 串扰可能是增殖性肾小球病的关键治疗策略。