Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice
Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice
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MyD88 的药理抑制可抑制实验小鼠肾小管上皮细胞的炎症并预防糖尿病肾病。
DOI：
10.1038/s41401-021-00766-6
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发表时间：
2022
影响因子：
8.2
通讯作者：
Liang Guang
中科院分区：
文献类型：
--
作者：
Zhang Qiuyan;Xu Sujing;Qian Jianchang;Yang Libin;Chen Pengqin;Wang Yi;Hu Xiang;Zhang Yali;Luo Wu;Liang Guang
新的证据表明，Toll样受体(Toll-like Receptor，TLR)介导的慢性炎症参与了糖尿病肾病的发生。髓系分化初级反应蛋白-88(MyD88)是天然免疫中除TLR3外的所有TLRs的必需接头蛋白。目前尚不清楚MyD88是否可以作为糖尿病肾病的治疗靶点。在这里，我们使用了一种新的小分子MyD88抑制剂LM8来研究MyD88在保护糖尿病肾脏免受炎症损伤方面的药理抑制作用。我们发现MyD88在STZ诱导的1型糖尿病小鼠肾脏的肾小管上皮细胞和高糖处理的大鼠肾小管上皮细胞NRK-52E中显著激活。在培养的肾小管上皮细胞中，我们发现LM8(2.5-10µM)或MyD88siRNA通过抑制MyD88-TLR4相互作用和下游的NF-κB激活来减轻高浓度葡萄糖诱导的炎症和纤维化反应。LM8(5 mg/kg，10 mg/kg，ig)显著减少1型和2型糖尿病小鼠的肾脏炎症和纤维化，并保护肾功能。这些肾脏保护作用与减少MyD88-TLR4复合体的形成、抑制NF-κB信号转导和阻止炎症因子的表达有关。总而言之，我们的结果表明，高血糖激活了MyD88信号级联，从而导致肾脏炎症、纤维化和功能障碍。药物抑制MyD88可能是减轻糖尿病肾病的一种治疗方法，而抑制剂LM8可能是这种治疗的潜在候选药物。
Emerging evidence shows that chronic inflammation mediated by toll-like receptors (TLRs) contributes to diabetic nephropathy. Myeloid differentiation primary-response protein-88 (MyD88) is an essential adapter protein of all TLRs except TLR3 in innate immunity. It is unclear whether MyD88 could be a therapeutic target for diabetic nephropathy. Here, we used a new small-molecule MyD88 inhibitor, LM8, to examine the pharmacological inhibition of MyD88 in protecting kidneys from inflammatory injury in diabetes. We showed that MyD88 was significantly activated in the kidney of STZ-induced type 1 diabetic mice in tubular epithelial cells as well as in high glucose-treated rat tubular epithelial cells NRK-52E. In cultured tubular epithelial cells, we show that LM8 (2.5-10 µM) or MyD88 siRNA attenuated high-concentration glucose-induced Inflammatory and fibrogenic responses through inhibition of MyD88-TLR4 interaction and downstream NF-κB activation. Treatment with LM8 (5,10 mg/kg, i.g.) significantly reduced renal inflammation and fibrosis and preserved renal function in both type 1 and type 2 diabetic mice. These renoprotective effects were associated with reduced MyD88-TLR4 complex formation, suppressed NF-κB signaling, and prevention of inflammatory factor expression. Collectively, our results show that hyperglycemia activates MyD88 signaling cascade to induce renal inflammation, fibrosis, and dysfunction. Pharmacological inhibition of MyD88 may be a therapeutic approach to mitigate diabetic nephropathy and the inhibitor LM8 could be a potential candidate for such therapy.