（5R）-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fcγ receptor signaling
（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 therapeuti...
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| Published in | 中国药理学报：英文版 Vol. 39; no. 1; pp. 107 - 116 |
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| Main Author | |
| Format | Journal Article |
| Language | English |
| Published |
2018
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| Online Access | Get full text |
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| Summary: | （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 FcγR11B in the kidney and spleen. In addition, the treatment restored the reduced expression of FcyRIIB on the surface of kidney effector cells, CD11b^＋ cells, and interfered with FcyR-dependent signaling, especially FcyRIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcγ receptor signaling. |
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| Bibliography: | （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 FcγR11B in the kidney and spleen. In addition, the treatment restored the reduced expression of FcyRIIB on the surface of kidney effector cells, CD11b^＋ cells, and interfered with FcyR-dependent signaling, especially FcyRIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcγ receptor signaling. triptolide; （5R）-5-hydroxytriptolide （LLDT-8）; prednisolone; glomerulonephritis; immune complexes; inflammation; Fcγ receptor signaling 31-1347/R |
| ISSN: | 1671-4083 1745-7254 |