School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Center for Scientific Research, Chengdu Medical College, Chengdu, China; Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China.
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Eur J Pharmacol. 2024 Dec 5;984:177028. doi: 10.1016/j.ejphar.2024.177028. Epub 2024 Oct 2.
Sepsis-induced acute kidney injury (SI-AKI) has become a focal point in nephrology research field due to its high mortality and potential progression to chronic kidney disease (CKD). The increase of M1 macrophages within renal tissue and their associated inflammatory responses are key contributors to renal inflammation and subsequent damage. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is abnormally activated during the onset of acute kidney injury (AKI). However, the relationship between the activation of this pathway and the increase in M1 macrophages has not been fully elucidated. This study investigated the protective effects and underlying mechanisms of the STING pathway-specific inhibitor C-176 on LPS-induced AKI, using an LPS and IFN-γ induced M1 macrophage model and an LPS-induced sepsis AKI mouse model. The in vivo results demonstrate that C-176 intervention can alleviate acute kidney injury and improve renal function by reducing macrophage infiltration in renal tissue, decreasing the proportion of M1 macrophages, and mitigating the inflammatory response. Additionally, in vitro results indicate that C-176 intervention inhibits the polarization of M0 macrophages to M1 macrophages, promotes their polarization to M2 macrophages, and reduces the amounts of pro-inflammatory cytokines such as IL-6 and TNF-α at both the protein and gene expression levels. The biological effects of C-176 are associated with the inhibition of STING-IRF3 signaling pathway activation. In summary, the findings of this study have certain scientific significance and application value for exploring the pathogenesis and treatment methods of SI-AKI.
脓毒症相关性急性肾损伤（SI-AKI）因其高死亡率且可能进展为慢性肾脏病（CKD）而成为肾脏病学研究领域的焦点。肾组织内 M1 巨噬细胞的增加及其相关炎症反应是导致肾炎症和随后损伤的关键因素。此外，环鸟苷酸-腺苷酸合成酶-干扰素基因刺激物（cGAS-STING）信号通路在急性肾损伤（AKI）发生时异常激活。然而，该通路的激活与 M1 巨噬细胞的增加之间的关系尚未完全阐明。本研究采用 LPS 和 IFN-γ诱导的 M1 巨噬细胞模型和 LPS 诱导的脓毒症 AKI 小鼠模型，探讨了 STING 通路特异性抑制剂 C-176 对 LPS 诱导的 AKI 的保护作用及其机制。体内研究结果表明，C-176 干预可通过减少肾组织中巨噬细胞浸润、降低 M1 巨噬细胞比例和减轻炎症反应，减轻急性肾损伤，改善肾功能。此外，体外研究结果表明，C-176 干预抑制 M0 巨噬细胞向 M1 巨噬细胞的极化，促进其向 M2 巨噬细胞的极化，并减少 IL-6 和 TNF-α 等促炎细胞因子在蛋白和基因表达水平的产生。C-176 的生物学效应与抑制 STING-IRF3 信号通路激活有关。综上所述，本研究结果对探索 SI-AKI 的发病机制和治疗方法具有一定的科学意义和应用价值。
