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

Abstract

(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.

• Authors: Qing Qi, Heng Li, Ze-Min Lin, Xiao-Qian Yang, Feng-Hua Zhu, Yu-Ting Liu, Mei-Juan Shao, Lu-Yao Zhang, Yan-Sheng Xu, Yu-Xi Yan, Lan-Lan Sun, Shi-Jun He, Wei Tang, Jian-Ping Zuo
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 39 Issue 1 Pg. 107-116 (Jan 2018) ISSN: 1745-7254 [Electronic] United States
• PMID: 28880016 (Publication Type: Journal Article)

Chemical References

• 5-hydroxytriptolide
• Complement C3
• Diterpenes
• Fc gamma receptor IIB
• Immunoglobulin G
• Immunosuppressive Agents
• Interleukin-17
• Interleukin-6
• Receptors, IgG
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Animals
• Anti-Glomerular Basement Membrane Disease (drug therapy)
• Complement C3 (metabolism)
• Diterpenes (administration & dosage, chemistry, therapeutic use)
• Immunoglobulin G (metabolism)
• Immunosuppressive Agents (administration & dosage, chemistry, therapeutic use)
• Inflammation (drug therapy)
• Interferon-gamma (metabolism)
• Interleukin-17 (metabolism)
• Interleukin-6 (metabolism)
• Kidney (pathology)
• Leukocytes (drug effects)
• Male
• Mice, Inbred Strains
• Receptors, IgG (genetics, metabolism)
• Signal Transduction (drug effects)
• Stereoisomerism
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation