脑啡肽酶缺失可减轻肾缺血再灌注损伤。

BACKGROUND: Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. METHOD: To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). RESULTS: Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. CONCLUSION: These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

背景：缺血再灌注（IR）损伤引起的急性肾损伤（AKI）仍然是围手术期的一个重大问题，目前尚无有效的治疗方法。Mindin 属于 Mindin/F-spondin 家族，参与炎症、增殖和细胞凋亡。先前的研究已经探讨了 Mindin 在肝和脑缺血性损伤中的生物学功能，但它在 AKI 中的作用尚不清楚。

方法：为了研究 Mindin 是否具有致病作用，使用 Mindin 敲除（KO）和野生型（WT）小鼠建立肾 IR 模型。在缺血 30 分钟和再灌注 24 小时后，检查肾组织学、血清肌酐和炎症反应，以评估肾损伤。在体外，在 Mindin 过表达或敲低以及载体细胞缺氧/复氧（HR）后，测量促炎因子和炎症信号通路。

结果：IR 后，WT 小鼠肾脏中的 Mindin 水平增加，Mindin 缺失对 IR 诱导的肾损伤提供了显著的保护作用，表现为血清肌酐和血尿素氮升高减轻，组织学改变减轻。Mindin 缺乏显著抑制肾 IR 损伤后的炎症细胞浸润、TNF-α 和 MCP-1 的产生。机制研究表明，Mindin 缺乏抑制 TLR4/JNK/NF-κB 信号激活。在体外，与载体细胞相比，HR 后 Mindin 过表达细胞中 TNF-α 和 MCP-1 的表达水平增加。此外，在 HR 刺激下，Mindin 过表达细胞中 TLR4/JNK/NF-κB 信号的激活增加，而在体外 HR 后，Mindin 敲低抑制 TLR4/JNK/NF-κB 信号的激活。进一步的研究表明，Mindin 蛋白与 TLR4 蛋白直接相互作用。而且，在人类肾积水患者的肾小管组织中大量表达了 Mindin 蛋白。

结论：这些数据表明，Mindin 通过调节炎症反应，成为肾 IR 损伤的关键调节因子。TLR4/JNK/NF-κB 信号可能介导了 Mindin 在这种肾缺血模型中的生物学功能。