Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation
Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation
复制标题
Kir6.2敲除通过增强NLRP3炎症小体激活加重脂多糖诱导的小鼠肝损伤
DOI：
10.1007/s00535-013-0823-0
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发表时间：
2014-04-01
影响因子：
6.3
通讯作者：
Hu, Gang
中科院分区：
文献类型：
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作者：
Du, Ren-Hong;Tan, Jun;Hu, Gang
背景：atp敏感的钾（K-ATP）通道将细胞代谢与电活动结合起来。虽然Kir6.2组成的K-ATP通道（Kir6.2/K-ATP通道）已被证明可以调节炎症，这是大多数肝脏疾病的常见原因，但其在肝损伤中的作用尚不清楚。方法：采用Kir6.2敲除小鼠制备lps诱导的肝损伤模型，研究Kir6.2/K-ATP通道在肝损伤中的作用。采用组织化学方法评价肝损伤程度。ELISA法检测促炎因子。western blot检测内质网应激和自噬情况。结果：我们发现，在LPS处理下，Kir6.2基因敲除显著促进肝脏淋巴细胞和中性粒细胞的浸润，显著升高血清丙氨酸转氨酶（ALT）水平。我们进一步发现，Kir6.2缺失增强了LPS攻击后NF-κB和NLRP3炎性体的激活，从而增加了促炎细胞因子IL-1β、IL-18和TNF-α的水平。用K-ATP通道打开剂iptakalim （IPT）治疗野生型小鼠可以通过减轻NLRP3炎症小体介导的炎症反应来保护lps诱导的肝损伤。此外，Kir6.2敲除诱导NLRP3炎症小体的激活加重了内质网（ER）应激、自噬和随后的肝细胞死亡。结论：Kir6.2缺失通过增强NLRP3炎症小体介导的炎症反应，加重了lps诱导的肝损伤。因此，Kir6.2/K-ATP通道可能是治疗和预防肝损伤的潜在候选靶点。
Background:ATP-sensitive potassium (K-ATP) channels couple cellular metabolism to electric activity. Although Kir6.2-composed K-ATP channel (Kir6.2/K-ATP channel) has been demonstrated to regulate inflammation, a common cause of most liver diseases, its role in liver injury remains elusive.Methods:Kir6.2 knockout mice were used to prepared LPS-induced liver injury model so as to investigate the role of Kir6.2/K-ATP channels in the injury. Histochemistry was applied to evaluate the extent of liver injury. Proinflammatory cytokines were analyzed by ELISA. Endoplasmic reticulum (ER) stress and autophagy were assessed by western blotting.Results:We showed that Kir6.2 knockout markedly promoted the infiltration of lymphocytes and neutrophils in liver and significantly elevated serum levels of alanine transaminase (ALT) in respond to LPS treatment. We further found that Kir6.2 deficiency enhanced the activation of NF-κB and NLRP3 inflammasome following LPS challenge, and thereby increased the levels of pro-inflammatory cytokines IL-1β, IL-18 and TNF-α. Treatment of wild-type mice with the K-ATP channel opener iptakalim (IPT) could protect against LPS-induced liver injury through attenuating NLRP3 inflammasome-mediated inflammatory responses. Furthermore, Kir6.2 knockout-induced activation of NLRP3 inflammasome aggravated endoplasmic reticulum (ER) stress, autophagy and subsequent hepatocyte death.Conclusion:Kir6.2 deficiency exacerbated LPS-induced liver injury by enhancing NLRP3 inflammasome-mediated inflammatory response. Thus, Kir6.2/K-ATP channel may be a potential candidate target for the treatment and prevention of liver injury.