Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice - 11/11/23
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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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | We designed a new small-molecule MD2 inhibitor, JM-9, which derived from curcumin. |
• | JM-9 attenuates renal injury, inflammation and fibrosis both in T1DM and T2DM. |
• | JM-9 inhibites MD2 activation and downstream pathway in diabetic nephropathy. |
• | JM-9 is expected to be a therapeutic candidate for diabetic nephropathy. |
Abbreviations : BUN, BSA, CMC-Na, COL4, DAB, DAPI, DKD, ddH2O, DMEM, DMSO, ESRD, FBS, GAPDH, H&E, HFD, HG, Icam1, IL1β, IL6, LFD, LPS, MD2, MTT, MyD88, NF-κB, OCT, PA, PAS, qPCR, RASIs, SDS-PAGE, T1DM, T2DM, TGFB1, TLRs, TNF-α
Keywords : Diabetic kidney disease, JM-9, Inflammation, Macrophage, Myeloid differentiation 2
Plan
Vol 168
Article 115660- décembre 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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