RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis.
RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis.
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DOI：
10.3389/fimmu.2022.900906
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
败血症是由全身感染引起的，是一个主要的健康问题，因为它是感染死亡的主要原因。它是世界范围内死亡的主要原因，并且对于脓毒症没有特异性有效的治疗方法。中性溶质通道水通道蛋白9（AQP 9）的基因缺失使细菌内毒素诱导的脓毒症小鼠模型中的氧化应激正常化并提高存活率。在本研究中，我们描述了一种新型小分子AQP 9抑制剂RG 100204在盲肠结扎穿孔（CLP）诱导的多微生物感染模型中的初步表征和作用。在体外，RG 100204在异位CHO细胞表达系统中阻断小鼠AQP 9 H2 O2渗透性，并消除LPS诱导的FaO肝癌细胞中超氧阴离子和一氧化氮增加。用RG100204（25 mg/kg p.o. CLP前和CLP后8 h再次给药）减轻CLP诱导的脓毒症引起的体温降低、心功能障碍（收缩和舒张）、肾功能障碍和肝细胞损伤。用RG 100204对CLP小鼠进行后处理还减轻了心脏功能障碍（收缩和舒张）、CLP诱导的脓毒症引起的肾功能障碍，但未显著减轻肝损伤或体温过低。最显著的发现是，在多微生物脓毒症发作后3 h经口给予RG 100204可减轻重度脓毒症引起的心脏和肾功能障碍。免疫印迹定量表明，RG 100204降低了NLRP 3炎性体途径的激活。此外，RG 100204处理的肺组织中的髓过氧化物酶活性降低。总之，这些结果表明，AQP 9可能是一个新的药物靶点在多微生物脓毒症。
Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.
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影响因子：
7.5
作者：
Rump K;Adamzik M
通讯作者：
Adamzik M
影响因子：
5.5
作者：
Bertolotti, Milena;Farinelli, Giada;Sitia, Roberto
通讯作者：
Sitia, Roberto
影响因子：
7.3
作者：
De Santis, Stefania;Fiorentino, Maria R.;Chieppa, Marcello
通讯作者：
Chieppa, Marcello
影响因子：
7.3
作者：
Mohammad S;Al Zoubi S;Collotta D;Krieg N;Wissuwa B;Ferreira Alves G;Purvis GSD;Norata GD;Baragetti A;Catapano AL;Solito E;Zechendorf E;Schürholz T;Correa-Vargas W;Brandenburg K;Coldewey SM;Collino M;Yaqoob MM;Martin L;Thiemermann C
通讯作者：
Thiemermann C
影响因子：
5.6
作者：
da Silva IV;Soveral G
通讯作者：
Soveral G