Wang Lu, Tang Wen, Jiang Long, Zhang Daquan, Wang Zhigao, Guo Rennan, Wang Jingjing, Xiao Dong
Department of Critical Care Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.
Front Mol Biosci. 2025 Jun 27;12:1571593. doi: 10.3389/fmolb.2025.1571593. eCollection 2025.
Sepsis-associated acute kidney injury (AKI) is a common complication of sepsis, which is a severe inflammatory disease with high mortality. The TGF-β/Smad signaling pathway plays an important role in the progression of sepsis, and targeting the TGF-β receptor II (TGFBR2) has been shown to ameliorate its effects. Ubiquitin-specific peptidase 11 (USP11) stabilizes TGFBR2 and enhances the TGF-β/Smad signaling pathway. In this study, we evaluated the effects of USP11 inhibition on sepsis-associated AKI.
A septic mouse model was established and treated with the USP11 inhibitor mitoxantrone. The expression of TGFBR2, phosphorylation of Smad3, as well as the levels of kidney injury markers, inflammatory cytokines, and oxidative stress markers, were measured in kidney tissues.
Elevated expressions of TGFBR2 and phosphorylated Smad3 were detected in the kidneys of septic mice, and mitoxantrone treatment was found to reduce the expression of TGFBR2 while suppressing the activation of Smad3. The drug also attenuated kidney injury while reducing inflammation and oxidative stress in the kidneys of septic mice.
USP11 inhibition by mitoxantrone ameliorated sepsis-associated AKI by downregulating TGFBR2/Smad3 signaling.
脓毒症相关急性肾损伤（AKI）是脓毒症的常见并发症，脓毒症是一种死亡率高的严重炎症性疾病。转化生长因子-β（TGF-β）/Smad信号通路在脓毒症进展中起重要作用，靶向转化生长因子-β受体II（TGFBR2）已被证明可改善其影响。泛素特异性肽酶11（USP11）可稳定TGFBR2并增强TGF-β/Smad信号通路。在本研究中，我们评估了USP11抑制对脓毒症相关AKI的影响。
建立脓毒症小鼠模型并用USP11抑制剂米托蒽醌进行治疗。检测肾组织中TGFBR2的表达、Smad3的磷酸化水平以及肾损伤标志物、炎性细胞因子和氧化应激标志物的水平。
在脓毒症小鼠的肾脏中检测到TGFBR2和磷酸化Smad3的表达升高，发现米托蒽醌治疗可降低TGFBR2的表达，同时抑制Smad3的激活。该药物还减轻了脓毒症小鼠肾脏的损伤，同时减少了炎症和氧化应激。
米托蒽醌抑制USP11通过下调TGFBR2/Smad3信号通路改善了脓毒症相关AKI。
