Zhang Jianjian, Zhang Yao, Feng Dengyuan, Zhou Hai, Gui Zeping, Zheng Ming, Hang Zhou, Gu Min, Tan Ruoyun
Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 210029, Nanjing, China.
Cell Death Discov. 2023 Jul 28;9(1):271. doi: 10.1038/s41420-023-01574-z.
Chronic allograft dysfunction (CAD) is a major factor that hinders kidney transplant survival in the long run. Epithelial-mesenchymal transition (EMT) has been confirmed to significantly contribute to interstitial fibrosis/tubular atrophy (IF/TA), which is the main histopathological feature of CAD. Aberrant expression of the regulator of calcineurin 1 (RCAN1), recognized as an endogenous inhibitor of the calcineurin phosphatase, has been shown to be extensively involved in various kidney diseases. However, it remains unclear how RCAN1.4 regulates IF/TA formation in CAD patients. Herein, an in vivo mouse renal transplantation model and an in vitro model of human renal tubular epithelial cells (HK-2) treated with tumor necrosis factor-α (TNF-α) were employed. Our results proved that RCAN1.4 expression was decreased in vivo and in vitro, in addition to the up-regulation of Yin Yang 1 (YY1), a transcription factor that has been reported to convey multiple functions in chronic kidney disease (CKD). Knocking in of RCAN1.4 efficiently attenuated chronic renal allograft interstitial fibrosis in vivo and inhibited TNF-α-induced EMT in vitro through regulating anti-oxidative stress and the calcineurin/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. In addition, suppression of YY1 mediated by shRNA or siRNA alleviated TNF-α-induced EMT through abolishing reactive species partly in an RCAN1.4-dependent manner. Notably, we confirmed that YY1 negatively regulated RCAN1.4 transcription by directly interacting with the RCAN1.4 promoter. In addition, histone deacetylase 2 (HDAC2) interacted with YY1 to form a multi-molecular complex, which was involved in TNF-α-induced RCAN1.4 transcriptional repression. Therefore, RCAN1.4 is suggested to be modulated by the YY1/HDAC2 transcription repressor complex in an epigenetic manner, which is a mediated nephroprotective effect partly through modulating O2⋅- generation and the calcineurin/NFATc1 signaling pathway. Thus, the YY1-RCAN1.4 axis constitutes an innovative target for IF/TA treatment in CAD patients.
慢性移植肾失功（CAD）是长期阻碍肾移植存活的主要因素。上皮-间质转化（EMT）已被证实对间质纤维化/肾小管萎缩（IF/TA）有显著影响，而IF/TA是CAD的主要组织病理学特征。钙调神经磷酸酶1调节因子（RCAN1）的异常表达被认为是钙调神经磷酸酶的内源性抑制剂，已被证明广泛参与各种肾脏疾病。然而，RCAN1.4如何调节CAD患者的IF/TA形成仍不清楚。在此，我们采用了体内小鼠肾移植模型和体外人肾小管上皮细胞（HK-2）用肿瘤坏死因子-α（TNF-α）处理的模型。我们的结果证明，除了阴阳1（YY1）上调外，RCAN1.4在体内和体外的表达均降低，YY1是一种转录因子，据报道在慢性肾脏病（CKD）中具有多种功能。通过调节抗氧化应激和钙调神经磷酸酶/活化T细胞核因子细胞质1（NFATc1）信号通路，敲入RCAN1.4可有效减轻体内慢性移植肾间质纤维化，并在体外抑制TNF-α诱导的EMT。此外，shRNA或siRNA介导的YY1抑制通过部分以RCAN1.4依赖性方式消除活性物质，减轻了TNF-α诱导的EMT。值得注意的是，我们证实YY1通过直接与RCAN1.4启动子相互作用来负调节RCAN1.4转录。此外，组蛋白去乙酰化酶2（HDAC2）与YY1相互作用形成多分子复合物，参与TNF-α诱导的RCAN1.4转录抑制。因此，提示RCAN1.4以表观遗传方式由YY1/HDAC2转录抑制复合物调节，这部分是通过调节O2⋅-生成和钙调神经磷酸酶/NFATc1信号通路介导的肾保护作用。因此，YY1-RCAN1.4轴构成了CAD患者IF/TA治疗的一个新靶点。
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