复旦大学陆利民等研究人员合作发现，USP11通过抑制KLF4的泛素降解以促进UUO小鼠肾小管细胞的焦亡和纤维化。2024年8月15日，《中国药理学报》杂志在线发表了这项成果。

研究人员表示，肾小管上皮细胞的焦亡会导致小管丧失和炎症，进而促进肾纤维化。转录因子Krüppel样因子4（KLF4）可以双向调节目标基因的转录。研究人员之前的工作表明，KLF4的持续升高是急性肾损伤（AKI）向慢性肾病（CKD）及肾纤维化转变的原因之一。

研究人员从翻译后调控的角度探索了肾小管上皮细胞焦亡的上游机制，重点研究了转录因子KLF4。小鼠接受单侧输尿管梗阻（UUO）手术，并于第7天或第14天被处死以获取肾组织。结果显示，UUO小鼠肾脏中由Caspase-1/GSDMD和Caspase-3/GSDME通路介导的肾小管上皮细胞焦亡随时间依赖性增加。

此外，研究人员发现UUO小鼠肾脏中KLF4的表达也呈时间依赖性上调。特异性敲除肾小管上皮细胞中的Klf4可缓解UUO诱导的焦亡和肾纤维化。在血管紧张素II（Ang II）处理的小鼠肾近端小管上皮细胞（MTEC）中，研究人员证明KLF4与Caspase-3和Caspase-1的启动子区域结合，并直接增加它们的转录。

此外，研究人员发现UUO小鼠肾脏中泛素特异性蛋白酶11（USP11）的表达增加。USP11对KLF4进行了去泛素化处理。敲除Usp11或在UUO手术前两周每周两次腹腔注射USP11抑制剂米托蒽醌（3 mg/kg）能显著缓解KLF4表达、焦亡和肾纤维化的增加。以上结果表明，肾小管细胞中USP11的表达增加抑制了KLF4的泛素降解，KLF4的升高通过启动肾小管细胞焦亡，促进了炎症和肾纤维化的发展。

附：英文原文

Title: USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation

Author: Wang, Xin, Xie, Xin, Ni, Jia-yun, Li, Jing-yao, Sun, Xi-ang, Xie, Hong-yan, Yang, Ning-hao, Guo, Heng-jiang, Lu, Li, Ning, Ming, Zhou, Li, Liu, Jun, Xu, Chen, Zhang, Wei, Wen, Yi, Shen, Qian, Xu, Hong, Lu, Li-min

Issue&Volume: 2024-08-15

Abstract: The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

DOI: 10.1038/s41401-024-01363-z

Source: https://www.nature.com/articles/s41401-024-01363-z