Liu Kaixuan, Hao Xiaoyu, Gao Yangfan, Cao Zhiyuan, Hou Min, Qin Lining, Song Yu, Wang Molin, Jiang Baichun, Liu Qiao, Zou Yongxin, Gong Yaoqin, Liu Guangyi, Sun Gongping
Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Cell Death Dis. 2024 Dec 18;15(12):915. doi: 10.1038/s41419-024-07299-w.
Acute kidney injury (AKI) caused by nephrotoxins, ischemia reperfusion (IR) or sepsis is associated with high morbidity and mortality. Unveiling new mechanisms underlying AKI can help develop new therapeutic strategy. Cullin 4B (CUL4B) is a scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Here, we demonstrate that CUL4B can protect kidneys from acute injury induced by cisplatin and IR. CUL4B is upregulated in mouse tubular epithelial cells (TECs) after cisplatin treatment or IR. Loss of CUL4B in kidneys exacerbates renal injury, inflammation, and apoptosis of TECs caused by cisplatin and IR. Transcriptome analysis reveals that Cul4b deficiency enhances injury-induced PAI-1 expression. CUL4B suppresses PAI-1 expression by promoting polyubiquitination and degradation of p53. Inhibition of either PAI-1 or p53 can prevent the aggravated renal injury and inflammation caused by loss of CUL4B. Our work has identified the kidney-protective role of CUL4B against acute injury.
由肾毒素、缺血再灌注（IR）或脓毒症引起的急性肾损伤（AKI）与高发病率和死亡率相关。揭示AKI潜在的新机制有助于开发新的治疗策略。Cullin 4B（CUL4B）是CUL4B-RING E3泛素连接酶（CRL4B）复合物中的一种支架蛋白。在此，我们证明CUL4B可保护肾脏免受顺铂和IR诱导的急性损伤。顺铂治疗或IR后，小鼠肾小管上皮细胞（TECs）中CUL4B上调。肾脏中CUL4B的缺失会加剧顺铂和IR引起的肾损伤、炎症以及TECs的凋亡。转录组分析显示，Cul4b缺陷会增强损伤诱导的PAI-1表达。CUL4B通过促进p53的多聚泛素化和降解来抑制PAI-1表达。抑制PAI-1或p53均可预防因CUL4B缺失引起肾损伤和炎症加重。我们的研究确定了CUL4B对急性损伤的肾脏保护作用。
