BACKGROUND AND PURPOSE Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis. Loganetin is a natural product with unknown bioactivities. Here, we identified a new protective effect and mechanism of Loganetin in a mouse model of AKI induced by rhabdomyolysis. EXPERIMENTAL APPROACH AKI was induced using glycerol by i.m. injection in mice models. Thirty minutes and 24 and 48 hr after injection of glycerol, the mice received 2 and 18 mg·kg-1 of Loganetin i.p. respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and Toll-like receptor 4 (TLR4) knockout mice. KEY RESULTS In the Loganetin treated group, kidney damage and mortality rate were declined, and blood urea nitrogen and serum creatinine were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, and the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down-regulated the expression of inflammation factors by suppressing TLR4 activity. CONCLUSION AND IMPLICATIONS All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.

中文翻译：

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Loganetin通过调节toll样受体4信号通路来预防横纹肌溶解引起的急性肾脏损伤。

背景与目的急性肾损伤（AKI）是一种快速的肾功能不全疾病，目前尚无有效的药物或疗法可改善预后。Loganetin是具有未知生物活性的天然产物。在这里，我们确定了横纹肌溶解诱导的小鼠AKI模型中Loganetin的新的保护作用和机制。实验方法通过甘油通过im注射在小鼠模型中诱导AKI。甘油注射后30分钟，24和48小时，小鼠分别腹腔注射Loganetin ip 2和18 mg·kg-1。然后收集小鼠的血液和肾脏进行各种生化和组织病理学研究。使用HK-2细胞和Toll样受体4（TLR4）敲除小鼠进行了Loganetin调节AKI的机制研究。主要结果在Loganetin治疗组中，肾脏损害和死亡率降低，血尿素氮和血清肌酐降低很多。Loganetin防止了甘油诱导的肾小管结构受损，并减少了皮质肾小管交界处的凋亡细胞。Loganetin在HK-2细胞中可以抑制NF-κB通路和促凋亡基因的表达。然而，TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。血尿素氮和血清肌酐要低得多。Loganetin防止了甘油诱导的肾小管结构受损，并减少了皮质肾小管交界处的凋亡细胞。Loganetin在HK-2细胞中可以抑制NF-κB通路和促凋亡基因的表达。然而，TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。血尿素氮和血清肌酐要低得多。Loganetin防止了甘油诱导的肾小管结构受损，并减少了皮质肾小管交界处的凋亡细胞。Loganetin在HK-2细胞中可以抑制NF-κB通路和促凋亡基因的表达。然而，TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。Loganetin防止了甘油诱导的肾小管结构受损，并减少了皮质肾小管交界处的凋亡细胞。Loganetin在HK-2细胞中可以抑制NF-κB通路和促凋亡基因的表达。然而，TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。Loganetin防止了甘油诱导的肾小管结构受损，并减少了皮质肾小管交界处的凋亡细胞。Loganetin在HK-2细胞中可以抑制NF-κB通路和促凋亡基因的表达。然而，TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。TLR4被特异的shRNA沉默，Loganetin在HK-2细胞中的抑制作用消失了。Loganetin还通过抑制TLR4活性来下调炎症因子的表达。结论和意义所有结果表明TLR4在AKI的发展中起着至关重要的作用，Loganetin通过抑制TLR4的活性和阻断JNK / p38途径来改善AKI，这为AKI的治疗提供了新的策略。