(5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fc gamma receptor signaling

doi:10.1038/aps.2017.88

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	(5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fc gamma receptor signaling
	Qi, Qing 2,3; Li, Heng 1,3; Lin, Ze-min 3; Yang, Xiao-qian 3; Zhu, Feng-hua 3; Liu, Yu-ting 1,3; Shao, Mei-juan 2,3; Zhang, Lu-yao 1,3; Xu, Yan-sheng 2,3; Yan, Yu-xi 1,3
刊名	ACTA PHARMACOLOGICA SINICA
	2018-01
卷号	39 期号:1 页码:107-116
关键词	triptolide (5R)-5-hydroxytriptolide (LLDT-8) prednisolone glomerulonephritis immune complexes inflammation Fc gamma receptor signaling
ISSN号	1671-4083
DOI	10.1038/aps.2017.88
文献子类	Article
英文摘要	(5R)-5-hydroxytriptolide (LLDT-8) is a novel triptolide analog that has been identified as a promising candidate for treating autoimmune diseases and has been shown to be effective in treating murine collagen-induced arthritis and lupus nephritis. In the present study, we investigated the therapeutic effect and possible mechanism of action of LLDT-8 in a murine anti-glomerular basement membrane (GBM) glomerulonephritis model. NZW mice were injected with rabbit anti-GBM serum (500 mu L, ip). The mice were orally treated with LLDT-8 (0.125 mg/kg, every other day) or a positive control prednisolone (2 mg/kg every day) for 14 d. Blood and urine samples as well as spleen and kidney tissues were collected for analyses. LLDT-8 treatment did not affect the generation of mouse anti-rabbit antibodies. LLDT-8 significantly reversed established proteinuria, improved renal histopathology and attenuated renal dysfunction in glomerulonephritis mice. Furthermore, LLDT-8 inhibited inflammation in the kidney evidenced by significantly decreasing C3 and IgG deposition, reducing the levels of the pathogenic cytokines TNF-alpha, IL-6, IL-17, and IFN-gamma, and reducing related chemokine expression and leukocyte infiltration in kidneys. Moreover, LLDT-8 treatment significantly increased the expression of Fc gamma RIIB in the kidney and spleen. In addition, the treatment restored the reduced expression of Fc gamma RIIB on the surface of kidney effector cells, CD11b(+) cells, and interfered with Fc gamma R-dependent signaling, especially Fc gamma RIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fc gamma receptor signaling.
资助项目	National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2014ZX09101002-001]
WOS关键词	SYSTEMIC-LUPUS-ERYTHEMATOSUS ; CHRONIC KIDNEY-DISEASE ; ANTI-GBM NEPHRITIS ; WILFORDII HOOK-F ; CRESCENTIC GLOMERULONEPHRITIS ; MATRIX METALLOPROTEINASES ; HETEROLOGOUS PHASE ; RENAL-DISEASE ; MRL/LPR MICE ; MACROPHAGES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000423867300010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272337]
专题	药理学第一研究室
通讯作者	He, Shi-jun; Tang, Wei; Zuo, Jian-ping
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, Shanghai 201203, Peoples R China; 4.Univ Yichun, Coll Chem & Biomed Engn, Yichun 336000, Peoples R China
推荐引用方式 GB/T 7714	Qi, Qing,Li, Heng,Lin, Ze-min,et al. (5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fc gamma receptor signaling[J]. ACTA PHARMACOLOGICA SINICA,2018,39(1):107-116.
APA	Qi, Qing.,Li, Heng.,Lin, Ze-min.,Yang, Xiao-qian.,Zhu, Feng-hua.,...&Zuo, Jian-ping.(2018).(5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fc gamma receptor signaling.ACTA PHARMACOLOGICA SINICA,39(1),107-116.
MLA	Qi, Qing,et al."(5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fc gamma receptor signaling".ACTA PHARMACOLOGICA SINICA 39.1(2018):107-116.