CircTMCO3 alleviates sepsis-induced acute kidney injury via regulating miR-218-5p/ZEB2 axis.

IF 2.7 3区医学 Q2 CRITICAL CARE MEDICINE SHOCK Pub Date : 2024-10-18 DOI:10.1097/SHK.0000000000002499

Yingfeng Gong, Na Wei, Peipei Shi, Gang Zhu

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Abstract

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 anti-apoptotic, antioxidant and anti-inflammatory activities. This indicates that increasing circTMCO3 expression might be a future therapeutic method for S-AKI.

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CircTMCO3 通过调节 miR-218-5p/ZEB2 轴减轻败血症诱发的急性肾损伤

背景：越来越多的证据表明，环状 RNA（circRNA）在败血症诱发的急性肾损伤（S-AKI）中发挥着关键作用。循环 TMCO3 被发现参与了卵巢癌的肿瘤微环境变化。本研究旨在探讨 CircTMCO3 是否在 S-AKI 中起作用，如果起作用，则阐明其分子机制：方法：分别在脂多糖（LPS）诱导的 HK-2 细胞和接受盲肠结扎和穿刺（CLP）治疗的小鼠肾组织中分析 circTMCO3 的表达。此外，还通过功能增益和/或缺失策略评估了 circTMCO3 在这两种模型中对 S-AKI 的影响及其相关机制：结果：在两种 S-AKI 模型中，circTMCO3 的表达均受到抑制。上调 circTMCO3 可减轻 LPS 诱导的 HK-2 细胞凋亡、氧化应激和炎症。相反，下调 circTMCO3 会加剧 LPS 诱导的 HK-2 细胞损伤。静脉注射 circTMCO3 慢病毒以增加 circTMCO3 的表达，可改善 S-AKI 小鼠的肾功能并减轻肾损伤，具体表现为血清肌酐和血尿素氮浓度下降、肾小管病理损伤改善、肾细胞凋亡减少、氧化应激和促炎细胞因子（TNF-α、IL-1β 和 IL-6）减轻。此外，circTMCO3直接靶向miR-218-5p，而miR-218-5p的模拟物在细胞模型中取消了circTMCO3的保护作用。研究发现，ZEB2是miR-218-5p的靶标；下调ZEB2不仅能逆转miR-218-5p抑制剂对S-AKI的影响，还能减轻体外上调circTMCO3介导的影响：结论：circTMCO3通过调节miR-218-5p/ZEB2轴，从而介导抗凋亡、抗氧化和抗炎活性，保护S-AKI。这表明，增加 circTMCO3 的表达可能是未来治疗 S-AKI 的一种方法。

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来源期刊

SHOCK 医学-外科

CiteScore

6.20

自引率

3.20%

发文量

199

审稿时长

1 months

期刊介绍： SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.