NLRP3 Inflammasome Knockout Mice Are Protected against Ischemic but Not Cisplatin-Induced Acute Kidney Injury
NLRP3 Inflammasome Knockout Mice Are Protected against Ischemic but Not Cisplatin-Induced Acute Kidney Injury
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DOI：
10.1124/jpet.113.205732
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Edelstein, Charles L.
中科院分区：
文献类型：
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作者：
Kim, Hyun-Jung;Lee, Dong Won;Edelstein, Charles L.
我们已经证明 caspase-1 是顺铂诱导的急性肾损伤 (AKI) 和缺血性 AKI 的介质。由于 caspase-1 在炎症小体中被激活，我们研究了顺铂诱导的缺血性 AKI 中的炎症小体。给小鼠注射顺铂或进行双侧肾蒂夹紧。顺铂诱导 AKI 后全肾的免疫印迹分析显示：1) 含有半胱天冬酶募集结构域 (ASC) 的凋亡相关 Speck 样蛋白增加，该蛋白是与核苷酸结合寡聚化结构域、富含亮氨酸重复序列和含有热蛋白结构域的蛋白 (NLRP) 1 或 3 复合形成炎症小体的主要蛋白； 2) caspase-1、caspase-5和NLRP1（NLRP1炎症小体的组成部分）活性增加； 3) NLRP3 呈增加趋势。为了确定 NLRP3 炎症小体是否在顺铂诱导的 AKI 中发挥有害作用，我们研究了 NLRP 敲除 (NLRP3(-/-)) 小鼠。在顺铂诱导的AKI中，与野生型小鼠相比，NALP3(-/-)小鼠的血尿素氮、血清肌酐、急性肾小管坏死评分和肾小管凋亡评分没有显着降低。我们之前已经证明了 caspase-1 在缺血性 AKI 中的有害作用。缺血性 AKI 中 NLRP3 升高，但 ASC 或 NLRP1 不升高。患有缺血性 AKI 的 NLRP3(-/-) 小鼠的血尿素氮、血清肌酐、急性肾小管坏死和凋亡评分显着低于野生型对照。与NLRP3(-/-)小鼠中的缺血性AKI相比，顺铂诱导的AKI的保护作用的差异不能用促炎细胞因子白细胞介素(IL)-1β、IL-6、趋化因子（C-X-C基序）配体1或肿瘤坏死因子α的差异来解释。 NLRP3 炎症小体是缺血性 AKI 的介质，但不是顺铂诱导的 AKI，因此对 NLRP1 炎症小体在顺铂诱导的 AKI 中的进一步研究应该会很有趣。
We have demonstrated that caspase-1 is a mediator of both cisplatin-induced acute kidney injury (AKI) and ischemic AKI. As caspase-1 is activated in the inflammasome, we investigated the inflammasome in cisplatin-induced and ischemic AKI. Mice were injected with cisplatin or subjected to bilateral renal pedicle clamping. Immunoblot analysis of whole kidney after cisplatin-induced AKI revealed: 1) an increase in apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), the major protein that complexes with nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing proteins (NLRP) 1 or 3 to form the inflammasome; 2) an increase in caspase-1 activity, caspase-5, and NLRP1, components of the NLRP1 inflammasome; and 3) a trend toward increased NLRP3. To determine whether the NLRP3 inflammasome plays an injurious role in cisplatin-induced AKI, we studied NLRP knockout (NLRP3(-/-)) mice. In cisplatin-induced AKI, the blood urea nitrogen, serum creatinine, acute tubular necrosis score, and tubular apoptosis score were not significantly decreased in NALP3(-/-) mice compared with wild-type mice. We have previously demonstrated the injurious role of caspase-1 in ischemic AKI. NLRP3, but not ASC or NLRP1, is increased in ischemic AKI. NLRP3(-/-) mice with ischemic AKI had significantly lower blood urea nitrogen, serum creatinine, and acute tubular necrosis and apoptosis scores than the wild-type controls. The difference in protection against cisplatin-induced AKI compared with ischemic AKI in NLRP3(-/-) mice was not explained by the differences in proinflammatory cytokines interleukin (IL)-1 beta, IL-6, chemokine (C-X-C motif) ligand 1, or tumor necrosis factor alpha. NLRP3 inflammasome is a mediator of ischemic AKI but not cisplatin-induced AKI, and further investigation of the NLRP1 inflammasome in cisplatin-induced AKI should prove interesting.