Gong Yingfeng, Wei Na, Shi Peipei, Zhu Gang
Graduate School of Bengbu Medical College, Bengbu City, Anhui Province, China.
Neurological Intensive Care Unit, Suzhou Municipal Hospital of Anhui Province, Suzhou City, Anhui Province, China.
Shock. 2025 Jan 1;63(1):168-175. doi: 10.1097/SHK.0000000000002499. Epub 2024 Oct 18.
Background: Growing evidence has found the critical role of circular RNAs (circRNAs) in sepsis-induced acute kidney injury (S-AKI). CircTMCO3 has been found to be involved in tumor microenvironment changes of ovarian cancer. This study aimed to explore whether circTMCO3 functions in S-AKI, and if so, to elucidate the molecular mechanism. Methods: CircTMCO3 expression was analyzed in lipopolysaccharide (LPS)-induced HK-2 cells and in the kidney tissues of mice treated with cecal ligation and puncture (CLP), respectively. Furthermore, the effects of circTMCO3 on S-AKI and the related mechanisms were evaluated in both models through gain- and/or loss-of-function strategies. Results: CircTMCO3 expression was suppressed in both S-AKI models. Upregulation of circTMCO3 mitigated LPS-induced apoptosis, oxidative stress, and inflammation in HK-2 cells. In contrast, circTMCO3 downregulation exacerbated LPS-induced injuries in HK-2 cells. Intravenous injection of circTMCO3 lentivirus to increase circTMCO3 expression improved renal function and attenuated kidney injury in S-AKI mice, as evidenced by the decrease in serum creatinine and blood urea nitrogen concentrations, amelioration of tubular pathological injury, reduction of renal cell apoptosis, and mitigation of oxidative stress and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, circTMCO3 directly targeted miR-218-5p, and the mimic of which abolished the protective effect of circTMCO3 in cell models. ZEB2 was identified to be a target of miR-218-5p; its downregulation not only reversed the impacts of miR-218-5p inhibitor on S-AKI, but also mitigated the effects mediated by circTMCO3 upregulation in vitro . Conclusions: CircTMCO3 protects against S-AKI by regulating miR-218-5p/ZEB2 axis, thereby mediating antiapoptotic, antioxidant, and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI.
越来越多的证据表明环状RNA（circRNAs）在脓毒症诱导的急性肾损伤（S-AKI）中起关键作用。已发现CircTMCO3参与卵巢癌的肿瘤微环境变化。本研究旨在探讨CircTMCO3是否在S-AKI中发挥作用，若如此，则阐明其分子机制。方法：分别分析脂多糖（LPS）诱导的HK-2细胞以及盲肠结扎穿刺（CLP）处理的小鼠肾组织中CircTMCO3的表达。此外，通过功能获得和/或功能缺失策略在两种模型中评估CircTMCO3对S-AKI的影响及其相关机制。结果：在两种S-AKI模型中，CircTMCO3表达均受到抑制。CircTMCO3上调减轻了LPS诱导的HK-2细胞凋亡、氧化应激和炎症。相反，CircTMCO3下调加剧了LPS诱导的HK-2细胞损伤。静脉注射CircTMCO3慢病毒以增加CircTMCO3表达可改善S-AKI小鼠的肾功能并减轻肾损伤，血清肌酐和血尿素氮浓度降低、肾小管病理损伤改善、肾细胞凋亡减少以及氧化应激和促炎细胞因子（TNF-α、IL-1β和IL-6）减轻均证明了这一点。此外，CircTMCO3直接靶向miR-218- 5p，其模拟物消除了CircTMCO3在细胞模型中的保护作用。ZEB2被确定为miR-218-5p的靶标；其下调不仅逆转了miR-218-5p抑制剂对S-AKI的影响，还减轻了体外CircTMCO3上调介导的作用。结论：CircTMCO3通过调节miR-218-5p/ZEB2轴来保护机体免受S-AKI，从而介导抗凋亡、抗氧化和抗炎活性。这表明增加CircTMCO3表达可能是未来治疗S-AKI的一种方法。
