RRC ID 77003
Author Wang M, Zhang Q, Lou S, Jin L, Wu G, Wu W, Tang Q, Wang Y, Long X, Huang P, Luo W, Liang G.
Title Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice.
Journal Biomed Pharmacother
Abstract Diabetic kidney disease (DKD) is one of the severe complications of diabetes mellitus-related microvascular lesions, which remains the leading cause of end-stage kidney disease. The genesis and development of DKD is closely related to inflammation. Myeloid differentiation 2 (MD2) mediates hyperlyciemia-induced renal inflammation and DKD development and is considered as a potential therapeutic target of DKD. Here, we identified a new small-molecule MD2 inhibitor, JM-9. In vitro, JM-9 suppressed high glucose (HG) and palmitic acid (PA)-induced inflammation in MPMs, accompanied by inhibition of MD2 activation and the downstream TLR4/MyD88-MAPKs/NFκB pro-inflammatory signaling pathway. Macrophage-derived factors increased the fibrotic and inflammatory responses in renal tubular epithelial cells, which were inhibited by treating macrophages with JM-9. Then, we investigated the therapeutic effects against DKD in streptozotocin-induced type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mouse models. Treatment with JM-9 prevented renal inflammation, fibrosis, and dysfunction by targeting MD2 in both T1DM and T2DM models. Our results show that JM-9, a new small-molecule MD2 inhibitor, protects against DKD by targeting MD2 and inhibiting MD2-mediated inflammation. In summary, JM-9 is a potential therapeutic agent for DKD.
Volume 168
Pages 115660
Published 2023-10-6
DOI 10.1016/j.biopha.2023.115660
PII S0753-3322(23)01458-0
PMID 37806092
IF 4.545
Mice RBRC02388