泛素特异性蛋白酶11通过表皮生长因子受体信号通路促进肾间质成纤维细胞的活化和增殖
Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.
摘要(中文译文)
慢性肾脏病是一个全球性的健康问题，其发病率呈上升趋势。既往研究表明，泛素特异性蛋白酶11（USP11）在肾脏纤维化过程中促进尿酸刺激的肾小管上皮细胞发生部分上皮-间充质转化。然而，其在肾间质成纤维细胞中的具体功能及机制仍不清楚。在本研究中，我们发现尿酸同样可在剂量梯度和时间梯度下上调培养成纤维细胞（NRK-49F）中USP11的水平，增幅约为3-4倍。通过基因和药理学手段敲低USP11可阻断肾间质成纤维细胞的活化，导致α-SMA和I型胶原表达减少约70-90%。USP11可增加表皮生长因子受体的磷酸化水平，从而激活其下游信号通路，包括磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B以及丝裂原活化蛋白激酶/细胞外调节蛋白激酶，进而激活核转录因子Snail和Slug。此外，USP11还可通过上调增殖细胞核抗原和细胞周期蛋白E的表达水平，影响NRK49F的增殖和迁移。因此，我们的研究提供了全面的证据，表明USP11是肾脏纤维化的一个有前景的靶点，抑制USP11可能是治疗慢性肾脏病的有效策略。
Abstract
Chronic kidney disease is a worldwide health problem, and its incidence is on the rise. It has previously been shown that ubiquitin-specific protease 11 (USP11) promotes partial epithelial-to-mesenchymal transition in uric acid-stimulated tubular epithelial cells during renal fibrosis. However, its specific function and mechanism in renal interstitial fibroblasts is still unknown. In this study, we found that uric acid could also upregulate the USP11 levels in cultured fibroblasts (NRK-49F) under dose gradient and time gradient, with an approximately 3-4 fold increase. Genetic and pharmacological depletion of USP11 blocked activation of renal interstitial fibroblasts leading to an approximately 70-90% reduction in α-SMA and collagen I expressions. USP11 increased the phosphorylation level of epidermal growth factor receptor, thereby activating its downstream signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B and mitogen-activated protein kinase /extracellular regulated protein kinases, which further activated nuclear transcription factors, Snail and Slug. Moreover, USP11 could also affect the proliferation and migration of NRK49F, by upregulating the expression levels of proliferating cell nuclear antigen and cyclin E. Thus, our study offers comprehensive evidence that USP11 is a promising target for kidney fibrosis and that inhibiting USP11 could be an effective strategy for treating chronic kideny disease.
如何引用
AMA
Xiaoyan Ma, Daofang Jiang, Xialin Li, Jinqing Li, Yan Hu, Peixin Wang, et al. Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.. Renal failure. 2026; doi:10.1080/0886022X.2026.2666452.
APA
Xiaoyan Ma, Daofang Jiang, Xialin Li, Jinqing Li, Yan Hu, Peixin Wang, et al (2026). Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.. Renal failure. https://doi.org/10.1080/0886022X.2026.2666452
GB/T 7714
Xiaoyan Ma, Daofang Jiang, Xialin Li, Jinqing Li, Yan Hu, Peixin Wang, et al. Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.[J]. Renal failure, 2026 doi:10.1080/0886022X.2026.2666452.
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