LCC18 , a benzamide‐linked small molecule, ameliorates IgA nephropathy in mice
| Autor: | Yusuke Suzuki, Shuk-Man Ka, Chung Yao Wu, Shin Ruen Yang, Akiko Takahata, Chih Yu Hsieh, Cheng-Hsu Chen, Hsu Shan Huang, Hsiao Wen Chiu, Debabrata Mukhopadhyay, Ann Chen, Kuo Feng Hua |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Inflammasomes urologic and male genital diseases Pathology and Forensic Medicine Nephropathy Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Immune system NLR Family Pyrin Domain-Containing 3 Protein Autophagy Animals Immunologic Factors Medicine business.industry Glomerulonephritis IGA Glomerulonephritis Inflammasome medicine.disease Protein kinase R Mice Inbred C57BL Disease Models Animal 030104 developmental biology Renal pathology 030220 oncology & carcinogenesis Benzamides Cancer research Female business medicine.drug |
| Zdroj: | The Journal of Pathology. 253:427-441 |
| ISSN: | 1096-9896 0022-3417 |
| Popis: | IgA nephropathy (IgAN), an immune complex-mediated process and the most common primary glomerulonephritis, can progress to end-stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring-fused 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC-15 hybridoma-derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX-2 axis-mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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