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Inhibition of MD2 by natural product-drived JM-9 attenuates renal inflammation and diabetic nephropathy in mice.

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.
AuthorsMinxiu Wang, Qianhui Zhang, Shuaijie Lou, Leiming Jin, Gaojun Wu, Wenqi Wu, Qidong Tang, Yi Wang, Xiaohong Long, Ping Huang, Wu Luo, Guang Liang
JournalBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 168 Pg. 115660 (Dec 2023) ISSN: 1950-6007 [Electronic] France
PMID37806092 (Publication Type: Journal Article)
CopyrightCopyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Topics
  • Mice
  • Animals
  • Diabetic Nephropathies (drug therapy, metabolism)
  • Diabetes Mellitus, Type 1 (complications, drug therapy)
  • Diabetes Mellitus, Type 2
  • Nephritis
  • Inflammation (drug therapy)

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