Abstract
Lupus nephritis (LN) is the most frequent phenotype in patients with systemic lupus erythematosus (SLE) and has a high rate of progression to end-stage renal disease, in spite of intensive treatment and maintenance therapies. Recent evidence suggests that protease-activated receptor-2 (PAR2) is a therapeutic target for glomerulonephritis. In this study, we performed a cell-based high-throughput screening and identified a novel potent PAR2 antagonist, punicalagin (PCG, a major polyphenol enriched in pomegranate), and evaluated the effects of PCG on LN. The effect of PCG on PAR2 inhibition was observed in the human podocyte cell line and its effect on LN was evaluated in NZB/W F1 mice. In the human podocyte cell line, PCG potently inhibited PAR2 (IC50 = 1.5 ± 0.03 µM) and significantly reduced the PAR2-mediated activation of ERK1/2 and NF-κB signaling pathway. In addition, PCG significantly decreased PAR2-induced increases in ICAM-1 and VCAM-1 as well as in IL-8, IFN-γ, and TNF-α expression. Notably, the intraperitoneal administration of PCG significantly alleviated kidney injury and splenomegaly and reduced proteinuria and renal ICAM-1 and VCAM-1 expression in NZB/W F1 mice. Our results suggest that PCG has beneficial effects on LN via inhibition of PAR2, and PCG is a potential therapeutic agent for LN.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the body produces antibodies against itself, resulting in major organ damage [1]
To identify novel Protease-activated receptor-2 (PAR2) antagonists, we performed a cell-based high-throughput screening with 1279 natural products in HaCaT cells expressing PAR2
PAR2 activation induces the production of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-α and IL-8, in various cell types [22,23]
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the body produces antibodies against itself, resulting in major organ damage [1]. Lupus nephritis (LN) is one of the most serious complications of SLE and is mainly induced by immune deposits in kidney glomeruli. PAR2 enhances the production of pro-inflammatory cytokines, by activating extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways and nuclear factor kappa B (NF-κB). This enhanced cytokine production leads to an increase in proliferation and inflammation in kidneys [13,14,15]. We identified a novel bioactive antagonist of PAR2, punicalagin (PCG), by a cell-based high-throughput screening approach. We characterized the effects of PCG in the human podocyte cell line and in lupus-prone NZB/W F1 mice
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