An Indole-2-Carboxamide Derivative, LG4, Alleviates Diabetic Kidney Disease Through Inhibiting MAPK-Mediated Inflammatory Responses.
An Indole-2-Carboxamide Derivative, LG4, Alleviates Diabetic Kidney Disease Through Inhibiting MAPK-Mediated Inflammatory Responses.
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一种 Indole-2-Carboxamide 衍生物 LG4 通过抑制 MAPK 介导的炎症反应来缓解糖尿病肾病
DOI：
10.2147/jir.s308353
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发表时间：
2021
影响因子：
4.5
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Qian J;Yin S;Ye L;Wang Z;Shu S;Mou Z;Xu M;Chattipakorn N;Liu Z;Liang G
已显示升高的炎症信号传导在糖尿病肾病（DKD）中起重要作用。我们以前开发了一种新的抗炎化合物LG 4。在本研究中，我们已经验证了LG 4可以通过抑制炎症来预防DKD的假设，并确定了潜在的机制。采用链脲佐菌素诱导的1型糖尿病小鼠建立DKD模型，观察LG 4对DKD的影响。为了鉴定LG 4的潜在靶点，合成了生物素连接的LG 4并进行蛋白质组微阵列筛选。在HG攻击的SV 40 MES 13细胞中研究LG 4的细胞机制。虽然LG 4治疗对体重和血糖水平没有影响，但它显著逆转了T1 DM小鼠高血糖诱导的肾脏病理变化和纤维化。重要的是，通过NF-κB激活和TNFα和IL-6过表达证实的高血糖诱导的肾脏炎症在LG 4治疗后得到了极大的改善。蛋白质体芯片筛选结果显示JNK和ERK是LG 4的直接结合蛋白。LG 4在体内和体外显著降低HG诱导的JNK和ERK磷酸化以及随后的NF-κB活化。此外，LG 4在存在JNK或ERK抑制剂的情况下在HG攻击的系膜细胞中没有显示出进一步的抗炎作用。LG 4通过抑制ERK/JNK介导的炎症反应对糖尿病小鼠肾脏具有保护作用，提示LG 4可能是糖尿病肾病的治疗药物。
Elevated inflammatory signaling has been shown to play an important role in diabetic kidney disease (DKD). We previously developed a new anti-inflammatory compound LG4. In the present study, we have tested the hypothesis that LG4 could prevent DKD by suppressing inflammation and identified the underlying mechanism. Streptozotocin-induced type 1 diabetic mice were used to develop DKD and evaluate the effects of LG4 against DKD. To identify the potential targets of LG4, biotin-linked LG4 was synthesized and subjected to proteome microarray screening. The cellular mechanism of LG4 was investigated in HG-challenged SV40MES13 cells. Although LG4 treatment had no effect on the body weight and blood glucose levels, it remarkably reversed the hyperglycemia-induced pathological changes and fibrosis in the kidneys of T1DM mice. Importantly, hyperglycemia-induced renal inflammation evidenced by NF-κB activation and TNFα and IL-6 overexpression was greatly ameliorated with LG4 treatment. Proteosome microarray screening revealed that JNK and ERK were the direct binding proteins of LG4. LG4 significantly reduced HG-induced JNK and ERK phosphorylation and subsequent NF-κB activation in vivo and in vitro. In addition, LG4 did not show further anti-inflammatory effect in HG-challenged mesangial cells with the presence of JNK or ERK inhibitor. LG4 showed renoprotective activity through inhibiting ERK/JNK-mediated inflammation in diabetic mice, indicating that LG4 may be a therapeutic agent for DKD.