TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia
TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia
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DOI：
10.1038/s41374-019-0304-z
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发表时间：
2020-02-01
影响因子：
5
通讯作者：
Simon, Felipe
中科院分区：
文献类型：
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作者：
Gatica, Sebastian;Villegas, Vicente;Simon, Felipe
急性肾损伤和内皮细胞通透性增高是严重脓毒症的主要特征，生存率低。瞬时受体电位melastatin 7（TRPM 7）钙通道抑制可能通过降低内皮细胞通透性来保护内毒素血症诱导的肾损伤。值得注意的是，TRPM 7抑制提高了内毒素血症动物的存活率。脓毒症是重症监护病房患者死亡的主要原因。在脓毒症期间，内皮渗透性严重增加，导致肾功能障碍和患者死亡。Ca 2+内流和随后的内皮细胞（EC）胞内[Ca 2 +]（i）的增加是建立内皮细胞高通透性的关键步骤。瞬时受体电位melastatin 7（TRPM 7）离子通道可渗透Ca 2+，并在广泛的细胞类型和组织中表达，包括EC和肾脏。然而，TRPM 7在脓毒症期间对内皮高通透性的作用仍然是难以捉摸的。因此，我们研究了TRPM 7在肾血管通透性过高、肾功能不全和内毒素血症引起的死亡率增加中的参与。我们的研究结果表明，内毒素通过TLR 4/NOX-2/ROS/NF-κ B B途径增加内皮细胞通透性和Ca 2+超载。此外，内毒素暴露显示下调VE-钙粘蛋白的表达，损害单层完整性并增强血管通透性。值得注意的是，内毒素诱导的内皮细胞通透性过高基本上被TRPM 7表达的药理学抑制和特异性抑制所抑制。内毒素可通过TLR 4/NOX-2/ROS/NF-κ B途径上调TRPM 7的表达，并诱导TRPM 7依赖的EC Ca 2+超载。值得注意的是，在内毒素血症动物中进行的体内实验表明，TRPM 7表达的药理学抑制和特异性抑制抑制肾血管通透性过高，防止肾功能障碍，并改善内毒素血症动物的存活率。因此，我们的研究结果表明，TRPM 7介导内毒素血症诱导的内皮通透性过高，肾功能障碍，并提高死亡率，揭示了一种新的分子靶点，用于治疗肾血管通透性过高和肾功能障碍，在内毒素血症，脓毒症，和其他炎症性疾病。
Acute kidney injury and endothelial hyperpermeability are main features observed during severe sepsis with low survival rate. Transient receptor potential melastatin 7 (TRPM7) calcium channel inhibition protects against endotoxemia-induced kidney injury potentially by means of endothelial hyperpermeability decreasing. Remarkably, TRPM7 inhibition improves survival in endotoxemic animals.Sepsis is the main cause of mortality in patients admitted to intensive care units. During sepsis, endothelial permeability is severely augmented, contributing to renal dysfunction and patient mortality. Ca2+ influx and the subsequent increase in intracellular [Ca2+](i) in endothelial cells (ECs) are key steps in the establishment of endothelial hyperpermeability. Transient receptor potential melastatin 7 (TRPM7) ion channels are permeable to Ca2+ and are expressed in a broad range of cell types and tissues, including ECs and kidneys. However, the role of TRPM7 on endothelial hyperpermeability during sepsis has remained elusive. Therefore, we investigated the participation of TRPM7 in renal vascular hyperpermeability, renal dysfunction, and enhanced mortality induced by endotoxemia. Our results showed that endotoxin increases endothelial hyperpermeability and Ca2+ overload through the TLR4/NOX-2/ROS/NF-kappa B pathway. Moreover, endotoxin exposure was shown to downregulate the expression of VE-cadherin, compromising monolayer integrity and enhancing vascular hyperpermeability. Notably, endotoxin-induced endothelial hyperpermeability was substantially inhibited by pharmacological inhibition and specific suppression of TRPM7 expression. The endotoxin was shown to upregulate the expression of TRPM7 via the TLR4/NOX-2/ROS/NF-kappa B pathway and induce a TRPM7-dependent EC Ca2+ overload. Remarkably, in vivo experiments performed in endotoxemic animals showed that pharmacological inhibition and specific suppression of TRPM7 expression inhibits renal vascular hyperpermeability, prevents kidney dysfunction, and improves survival in endotoxemic animals. Therefore, our results showed that TRPM7 mediates endotoxemia-induced endothelial hyperpermeability, renal dysfunction, and enhanced mortality, revealing a novel molecular target for treating renal vascular hyperpermeability and kidney dysfunction during endotoxemia, sepsis, and other inflammatory diseases.