Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice

• 作者: Qiu-yan Zhang Su-jing Xu Jian-chang Qian Li-bin Yang Peng-qin Chen Yi Wang Xiang Hu Ya-li Zhang Wu Luo Guang Liang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: Endocrine Pharmacology
• 页码范围: 354-366
• 页数: 13页
• 语种: 英文

摘要

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.