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

• 来源期刊: 中国药理学报（英文版）
• 关键词: triptolide (5R)-5-hydroxytriptolide (LLDT-8) prednisolone glomerulonephritis immune complexes inflammation Fcγ receptor signaling
• 年，卷（期）: 2018,（1）
• 页码范围: 107-116
• 页数: 10页
• 语种: 英文
• DOI: 10.1038/aps.2017.88

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 μL,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-α,IL-6,IL-17,and IFN-γ,and reducing related chemokine expression and leukocyte infiltration in kidneys.Moreover,LLDT-8 treatment significantly increased the expression of FcγRIIB in the kidney and spleen.In addition,the treatment restored the reduced expression of FcγRIIB on the surface of kidney effector cells,CD11b+ cells,and interfered with FcγR-dependent signaling,especially FcγRIIB-mediated downstream kinases,such as BTK.These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcγ receptor signaling.