Ibudilast Attenuates Folic Acid-Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways.
Ibudilast Attenuates Folic Acid-Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways.
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DOI：
10.3389/fphar.2021.650283
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhai XY
中科院分区：
文献类型：
--
作者：
Li X;Zou Y;Fu YY;Xing J;Wang KY;Wan PZ;Wang M;Zhai XY
叶酸（FA）诱导的肾小管损伤是一种常见的急性肾损伤（阿基）模型，其特征在于广泛的炎症。由于炎性半胱天冬酶的激活，细胞死亡的促炎形式Pyroptosis参与阿基进展。异丁司特是一种TLR 4拮抗剂，已在临床上用于对哮喘发挥抗炎作用。然而，研究人员尚未探索异丁司特是否通过抑制炎症对阿基发挥保护作用。在本研究中，异丁司特逆转了小鼠中FA诱导的阿基，如血清肌酐和尿素氮水平降低所示，并改善了肾脏病理学，以及肾损伤标志物-1的下调。此外，异丁司特显著增加抗炎因子IL-10的产生，同时抑制促炎细胞因子TNF-α的分泌和巨噬细胞浸润。此外，在损伤的肾脏中，异丁司特降低了炎性小体标记物（NLRP 3）和脓毒性相关蛋白（caspase-1、IL-1-β、IL-18和GSDMD裂解）的水平，并减少了TUNEL阳性细胞的数量。进一步的机制研究表明，异丁司特给药抑制FA诱导的TLR 4上调，阻断NF-κB核转位，并降低NF-κB和IκBα、p38、ERK和JNK的磷酸化。因此，本研究证实了异丁司特对小鼠中FA诱导的阿基的保护作用，并表明可能通过抑制TLR 4介导的NF-κB和MAPK信号通路来减少焦亡和炎症，从而实现保护作用。
Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-β, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.
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