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.

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

Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China;Medical Research Center,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325035,China;School and Hospital of Stomatology,Wenzhou Medical University,Wenzhou 325027,China;Department of Endocrinology,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325035,China;School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou 311399,China;Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325001,China

中国药理学报（英文版）

[1]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-.Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice)[J].中国药理学报（英文版）,2022(02):354-366

renoprotective

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