Renal fibrosis is the pathological hallmark of chronic kidney disease that is influenced by numerous factors. Arrest of renal tubular epithelial cells (RTECs) in G2/M phase is closely correlated with the progression of renal fibrosis; however, the mechanisms mediating these responses remain poorly defined. In this study, we observed that human leukocyte antigen-F adjacent transcript 10 (FAT10) deficiency abolished hypoxia-induced upregulation of checkpoint kinase 1 (CHK1) expression in RTECs derived from FAT10^+/+ and FAT10^−/− mice. Further investigations revealed that FAT10 contributes to CHK1-mediated G2/M arrest and production of pro-fibrotic cytokines in RTECs exposed to hypoxia. Mechanistically, FAT10 directly interacted with and stabilized the deubiquitylating enzyme ubiquitin specific protease 7 (USP7) to mediate CHK1 upregulation, thereby promoting CHK1-mediated G2/M arrest in RTECs. In animal model, FAT10 expression was upregulated in the obstructed kidneys of mice induced by unilateral ureteric obstruction injury, and FAT10^−/− mice exhibited reduced unilateral ureteric obstruction injury induced-renal fibrosis compared with FAT10^+/+ mice. Furthermore, in a cohort of patients with calculi-related chronic kidney disease, upregulated FAT10 expression was positively correlated with renal fibrosis and the USP7/CHK1 axis. These novel findings indicate that FAT10 prolongs CHK1-mediated G2/M arrest via USP7 to promote renal fibrosis, and inhibition of the FAT10/USP7/CHK1 axis might be a plausible therapeutic approach to alleviate renal fibrosis in chronic kidney disease.

中文翻译：

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泛素样蛋白 FAT10 通过稳定 USP7 来延长肾小管上皮细胞中 CHK1 介导的 G2/M 期停滞，从而促进肾纤维化

肾纤维化是受多种因素影响的慢性肾脏病的病理标志。G2/M期肾小管上皮细胞（RTECs）阻滞与肾纤维化进程密切相关；然而，调解这些反应的机制仍然不明确。在这项研究中，我们观察到人类白细胞抗原-F 邻近转录物 10 (FAT10) 缺陷消除了缺氧诱导的来自 FAT10 ^+/+和 FAT10 ^{-/-的 RTEC 中检查点激酶 1 (CHK1) 表达的上调}老鼠。进一步的研究表明，FAT10 有助于 CHK1 介导的 G2/M 停滞和暴露于缺氧的 RTEC 中促纤维化细胞因子的产生。从机制上讲，FAT10 直接与去泛素化酶泛素特异性蛋白酶 7 (USP7) 相互作用并使其稳定，以介导 CHK1 上调，从而促进 RTEC 中 CHK1 介导的 G2/M 期停滞。在动物模型中，FAT10 表达在单侧输尿管梗阻损伤诱导的小鼠梗阻肾脏中上调，与 FAT10 ^{+/+相比，FAT10 -/-}小鼠表现出单侧输尿管梗阻损伤诱导的肾纤维化减少老鼠。此外，在结石相关慢性肾病患者队列中，上调的 FAT10 表达与肾纤维化和 USP7/CHK1 轴呈正相关。这些新发现表明 FAT10 通过 USP7 延长 CHK1 介导的 G2/M 阻滞以促进肾纤维化，并且抑制 FAT10/USP7/CHK1 轴可能是减轻慢性肾病肾纤维化的一种合理的治疗方法。