Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury.
Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury.
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DOI：
10.1016/j.kint.2023.02.026
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发表时间：
2023-03
影响因子：
19.6
通讯作者：
Ji Young Kim;J. Silvaroli;G. Vásquez Martínez;Bijay Bisunke;Alanys V. Luna Ramirez;Laura A Jayne;M. Feng;Bhavya Girotra;Shirely M. Acosta Martinez;Corynne R. Vermillion;Isaac Z. Karel;Nicholas Ferrell;N. Weisleder;Sangwoon Chung;J. Christman;C. Brooks;S. Madhavan;K. Hoyt;R. Cianciolo;A. Satoskar;D. Zepeda-Orozco;J. Sullivan;A. Davidson;A. Bajwa;Navjotsingh Pabla
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文献类型：
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作者：
Ji Young Kim;J. Silvaroli;G. Vásquez Martínez;Bijay Bisunke;Alanys V. Luna Ramirez;Laura A Jayne;M. Feng;Bhavya Girotra;Shirely M. Acosta Martinez;Corynne R. Vermillion;Isaac Z. Karel;Nicholas Ferrell;N. Weisleder;Sangwoon Chung;J. Christman;C. Brooks;S. Madhavan;K. Hoyt;R. Cianciolo;A. Satoskar;D. Zepeda-Orozco;J. Sullivan;A. Davidson;A. Bajwa;Navjotsingh Pabla
转录谱研究已经确定了急性肾损伤（AKI）期间小管上皮细胞中上调的几个保护基因。识别上游转录调控因子可能会导致治疗策略的发展，从而增强修复过程。SOX9是一种转录因子，在包括肾脏在内的多个器官中控制胚胎发育过程中的细胞命运和成体组织稳态。SOX9在成人肾脏中表达较低；然而，应激条件可触发其在小管上皮细胞中的转录上调。SOX9在AKI早期发挥保护作用，在恢复阶段促进修复。为了确定在小管上皮细胞中驱动SOX9上调的上游转录调节因子，我们使用了无偏倚的转录因子筛选方法。初步筛选和验证研究表明，锌指蛋白24 （ZFP24）调控小管上皮细胞中SOX9的上调。ZFP24是一种Cys2-His2 （C2H2）锌指蛋白，对少突胶质细胞成熟和髓鞘形成至关重要；然而，它在肾脏或SOX9调节中的作用仍然未知。在这里，我们发现小管上皮ZFP24基因消融加剧了缺血、横纹肌溶解和顺铂相关AKI。重要的是，ZFP24基因缺失导致受损小管上皮细胞中SOX9上调受到抑制。染色质免疫沉淀和启动子荧光素酶测定证实，ZFP24结合到小鼠和人类SOX9启动子的特定位点。重要的是，CRISPR/ cas9介导的SOX9启动子ZFP24结合位点突变参与了AKI期间SOX9上调的抑制。因此，我们的研究结果确定ZFP24是通过上调SOX9保护小管上皮细胞的关键应激应答转录因子。
Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein, is essential for oligodendrocyte maturation and myelination; however, its role in the kidneys or in SOX9 regulation remains unknown. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoterin vivoled to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.