Glomerular Injury Is Exacerbated in Lupus-Prone MRL/lpr Mice Treated with a Protease-Activated Receptor 2 Antagonist.

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies, which causes multi-organ injury such as lupus nephritis. SLE is associated with hypercoagulability. Activated coagulation factors such as tissue factor and VIIa complex and factor Xa activate protease-activated receptor 2 (PAR2). PAR2 promotes cytokine production through mitogen-activated protein kinase or nuclear factor kappa B signaling, and previous reports demonstrated that inhibition of PAR2 alleviated kidney injuries such as diabetic kidney disease and renal fibrosis in animal models. However, the involvement of PAR2 in the pathogenesis of SLE remains unclear. We therefore administered a selective PAR2 peptide antagonist, FSLLRY-NH2, to SLE-prone 4-month-old MRL-Faslpr mice for 4 weeks. Treatment with FSLLRY-NH2 caused the significant increases in the glomerular mesangial proliferation, glomerular deposition of both immunoglobulin G and complement factor C3d, and glomerular infiltration of Mac2-positive macrophages and CD3-positive T cells, compared with MRL-Faslpr mice treated with saline. In addition, the treatment with the PAR2 antagonist increased renal expression levels of tumor necrosis factor-α (Tnfa) and monocyte chemoattractant protein 1 (Mcp1) mRNA. Collectively, these results suggest that inhibition of PAR2 may increase the severity of inflammation in lupus nephritis; namely, opposite to previous observations, PAR2 has anti-inflammatory properties. We propose that activation of PAR2 could serve as a potential therapeutic option for patients with SLE.

Nicotinamide alleviates kidney injury and pregnancy outcomes in lupus-prone MRL/lpr mice treated with lipopolysaccharide.

Systemic lupus erythematosus (SLE) increases the risk of preterm birth and preeclampsia (PE). The flares of SLE during pregnancy or after delivery are also problematic. We have previously demonstrated that nicotinamide (NAM), a non-teratogenic amide of vitamin B3, reduces inflammation and oxidative stress and improves PE-like phenotype and pregnancy outcomes in the mouse models of PE. The present study aimed to establish a model to investigate the pregnancy outcomes and flares of SLE in pregnant mice with SLE and to examine whether NAM is beneficial to pregnant mice with SLE. We used pregnant and non-pregnant lupus-prone MRL/lpr mice treated with or without a Toll-like receptor (TLR) ligand lipopolysaccharide (LPS) because TLR4 signaling reportedly exacerbates SLE and pregnancy; MRL/+ mice were used as controls. Blood pressure (BP) and urinary albumin excretion were increased only in the pregnant MRL/lpr-LPS mice. LPS together with pregnancy exacerbated glomerulonephritis, and the most severe inflammation was observed in the kidneys of the pregnant MRL/lpr-LPS mice. The shortening of pregnancy periods, increase in fetal demise percentage, and reduction in fetal weight were observed only in the pregnant MRL/lpr-LPS mice. NAM improved BP and kidney injury, prolonged pregnancy periods, and improved fetal growth in the pregnant MRL/lpr-LPS mice. The results suggest that SLE patients are prone to develop poor pregnancy outcome, and likely develop severe nephropathy and kidney inflammation. NAM may be a novel therapeutic option that improves kidney injury and pregnancy outcomes, thereby benefiting pregnant patients with SLE.