ASC in Renal Collecting Duct Epithelial Cells Contributes to Inflammation and Injury after Unilateral Ureteral Obstruction
ASC in Renal Collecting Duct Epithelial Cells Contributes to Inflammation and Injury after Unilateral Ureteral Obstruction
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DOI：
10.1016/j.ajpath.2014.01.014
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发表时间：
2014-05-01
影响因子：
6
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
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作者：
Komada, Takanori;Usui, Fumitake;Takahashi, Masafumi
炎症在慢性肾脏病的病理生理学特征中起着至关重要的作用;然而，慢性肾脏病过程中的炎症机制仍不清楚。最近的证据表明，由组织损伤引发的无菌炎症是通过称为炎性体的多蛋白复合物介导的。因此，我们使用小鼠单侧输尿管梗阻（UUO）模型研究炎性小体在慢性肾脏疾病发展中的作用。UUO后肾脏炎症相关分子表达上调。含有半胱天冬酶募集结构域缺陷的凋亡相关斑点样蛋白显著降低炎症反应，如炎性细胞浸润和细胞因子表达，并改善随后的肾损伤和纤维化。此外，在UUO处理的肾脏的集合管（CD）上皮细胞中，含有胱天蛋白酶募集结构域的骨化相关斑点样蛋白特异性上调。体外实验表明，细胞外三磷酸腺苷（ATP）通过P2 X（7）-钾外流和活性氧依赖性途径诱导CD上皮细胞中的炎性小体活化。这些结果证明了慢性肾脏疾病过程中炎症反应的分子基础，并表明CD炎性小体是预防慢性肾脏疾病进展的潜在治疗靶点。
Inflammation plays a crucial role in the pathophysiologicat characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a muttiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X(7)-potassium efflux and reactive oxygen species dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.