The mortality rate linked with nephrotic syndrome (NS) is quite high. The renal tubular injury influences the response of NS patients to steroid treatment. KN motif and ankyrin repeat domains 2 (KANK2) regulates actin polymerization, which is required for renal tubular cells to maintain their function. In this study, we found that the levels of KANK2 in patients with NS were considerably lower than those in healthy controls, especially in NS patients with acute kidney injury (AKI). To get a deeper understanding of the KANK2 transcriptional control mechanism, the core promoter region of the KANK2 gene was identified. KANK2 was further found to be positively regulated by E2F Transcription Factor 1 (E2F1), Transcription Factor AP-2 Gamma (TFAP2C), and Nuclear Respiratory Factor 1 (NRF1), both at mRNA and protein levels. Knocking down E2F1, TFAP2C, or NRF1 deformed the cytoskeleton of renal tubular cells and reduced F-actin content. EMSA and ChIP assays confirmed that all three transcription factors could bind to the upstream promoter transcription site of KANK2 to transactivate KANK2 in renal tubular epithelial cells. Our study suggests that E2F1, TFAP2C, and NRF1 play essential roles in regulating the KANK2 transcription, therefore shedding fresh light on the development of putative therapeutic options for the treatment of NS patients.

与肾病综合征（NS）相关的死亡率相当高。肾小管损伤影响NS患者对类固醇治疗的反应。KN 基序和锚蛋白重复结构域 2 (KANK2) 调节肌动蛋白聚合，这是肾小管细胞维持其功能所必需的。在这项研究中，我们发现 NS 患者中 KANK2 的水平显着低于健康对照，尤其是伴有急性肾损伤（AKI）的 NS 患者。为了更深入地了解 KANK2 转录控制机制，鉴定了 KANK2 基因的核心启动子区域。进一步发现 KANK2 在 mRNA 和蛋白质水平上均受到 E2F 转录因子 1 (E2F1)、转录因子 AP-2 Gamma (TFAP2C) 和核呼吸因子 1 (NRF1) 的正向调节。敲低 E2F1、TFAP2C 或 NRF1 会使肾小管细胞的细胞骨架变形并减少 F-肌动蛋白含量。EMSA 和 ChIP 测定证实，所有三种转录因子均可与 KANK2 的上游启动子转录位点结合，从而反式激活肾小管上皮细胞中的 KANK2。我们的研究表明，E2F1、TFAP2C 和 NRF1 在调节 KANK2 转录中发挥着重要作用，因此为 NS 患者治疗的假定治疗方案的开发提供了新的线索。