Industrially produced trans-fatty acids are potent promoters of DNA damage-induced apoptosis.

trans-Fatty acids (TFAs) are unsaturated fatty acids harboring at least one carbon-carbon double bond in trans configuration, which are categorized into two groups according to their origin: industrial and ruminant TFAs, hereafter called iTFAs and rTFAs, respectively. Numerous epidemiological studies have shown a specific link of iTFAs to various diseases, such as cardiovascular and neurodegenerative diseases. However, there is little evidence for underlying mechanisms that can explain the specific toxicity of iTFAs, and how to mitigate their toxicity. Herein, we show that iTFAs, including elaidic acid (EA) and linoelaidic acid, but not rTFAs, facilitate apoptosis induced by doxorubicin (Dox), triggering DNA double-strand breaks. We previously established that EA promotes Dox-induced apoptosis by accelerating c-Jun N-terminal kinase (JNK) activation through mitochondrial reactive oxygen species (ROS) overproduction. Consistently, iTFAs specifically enhanced Dox-induced JNK activation. Furthermore, Dox-induced pro-apoptotic signaling by iTFAs was blocked in the presence of oleic acid (OA), the geometrical cis isomer of EA. These results demonstrate that iTFAs specifically exert their toxicity during DNA damage-induced apoptosis, which could be effectively suppressed by OA. Our study provides evidence for understanding the difference in toxic actions between TFA species, and for new strategies to prevent and combat TFA-related diseases.

Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs.

trans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon-carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.

A non-canonical vitamin K cycle is a potent ferroptosis suppressor.

Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone3-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.

Methylglyoxal Induces Inflammation, Metabolic Modulation and Oxidative Stress in Myoblast Cells.

Uremic sarcopenia is a serious clinical problem associated with physical disability and increased morbidity and mortality. Methylglyoxal (MG) is a highly reactive, dicarbonyl uremic toxin that accumulates in the circulatory system in patients with chronic kidney disease (CKD) and is related to the pathology of uremic sarcopenia. The pathophysiology of uremic sarcopenia is multifactorial; however, the details remain unknown. We investigated the mechanisms of MG-induced muscle atrophy using mouse myoblast C2C12 cells, focusing on intracellular metabolism and mitochondrial injury. We found that one of the causative pathological mechanisms of uremic sarcopenia is metabolic flow change to fatty acid synthesis with MG-induced ATP shortage in myoblasts. Evaluation of cell viability revealed that MG showed toxic effects only in myoblast cells, but not in myotube cells. Expression of mRNA or protein analysis revealed that MG induces muscle atrophy, inflammation, fibrosis, and oxidative stress in myoblast cells. Target metabolomics revealed that MG induces metabolic alterations, such as a reduction in tricarboxylic acid cycle metabolites. In addition, MG induces mitochondrial morphological abnormalities in myoblasts. These changes resulted in the reduction of ATP derived from the mitochondria of myoblast cells. Our results indicate that MG is a pathogenic factor in sarcopenia in CKD.

What's New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists, have advanced, their efficacy is still limited. Thus, a deeper understanding of the molecular mechanisms of DKD onset and progression is necessary for the development of new and innovative treatments for DKD. The complex pathogenesis of DKD includes various different pathways, and the mechanisms of DKD can be broadly classified into inflammatory, fibrotic, metabolic, and hemodynamic factors. Here, we summarize the recent findings in basic research, focusing on each factor and recent advances in the treatment of DKD. Collective evidence from basic and clinical research studies is helpful for understanding the definitive mechanisms of DKD and their regulatory systems. Further comprehensive exploration is warranted to advance our knowledge of the pathogenesis of DKD and establish novel treatments and preventive strategies.

Solvent-free autocatalytic supramolecular polymerization.

Solvent-free chemical manufacturing is one of the awaited technologies for addressing an emergent issue of environmental pollution. Here, we report solvent-free autocatalytic supramolecular polymerization (SF-ASP), which provides an inhibition-free template-assisted catalytic organic transformation that takes great advantage of the fact that the product (template) undergoes a termination-free nucleation-elongation assembly (living supramolecular polymerization) under solvent-free conditions. SF-ASP allows for reductive cyclotetramerization of hydrogen-bonding phthalonitriles into the corresponding phthalocyanines in exceptionally high yields (>80%). SF-ASP requires the growing polymer to form hexagonally packed crystalline fibres, which possibly preorganize the phthalonitriles at their cross-sectional edges for their efficient transformation. With metal oleates, SF-ASP produces single-crystalline fibres of metallophthalocyanines again in exceptionally high yields, which grow in both directions without terminal coupling until the phthalonitrile precursors are completely consumed. By taking advantage of this living nature of polymerization, multistep SF-ASP without/with metal oleates allows for the precision synthesis of multi-block supramolecular copolymers.

Myeloid cell-derived coagulation tissue factor is associated with renal tubular damage in mice fed an adenine diet.

Patients with chronic kidney disease (CKD) commonly exhibit hypercoagulability. Increased levels of uremic toxins cause thrombogenicity by increasing tissue factor (TF) expression and activating the extrinsic coagulation cascade. TF is induced in monocytes and macrophages under pathological conditions, such as inflammatory diseases. However, the role of monocyte myeloid cell TF in CKD progression remains unclear. We aimed to clarify this issue, and the present study found that patients with CKD had elevated levels of D-dimer, a marker of fibrin degradation, which was associated with decreased estimated glomerular filtration rate and increased serum levels of uremic toxins, such as indoxyl sulfate. In vitro studies showed that several uremic toxins increased cellular TF levels in monocytic THP-1 cells. Mice with TF specifically deleted in myeloid cells were fed an adenine diet to cause uremic kidney injury. Myeloid TF deletion reduced tubular injury and pro-inflammatory gene expression in the kidneys of adenine-induced CKD but did not improve renal function as measured by plasma creatinine or blood urea nitrogen. Collectively, our findings suggest a novel concept of pathogenesis of coagulation-mediated kidney injury, in which elevated TF levels in monocytes under uremic conditions is partly involved in the development of CKD.

Effect of uremic toxins on hippocampal cell damage: analysis in vitro and in rat model of chronic kidney disease.

One third of the patients with chronic kidney disease (CKD) develop cognitive impairment, which is also an independent risk factor for mortality. However, the concise mechanism of cerebro-renal interaction has not been clarified. The present study examines the effects of uremic toxins on neuronal cells and analyzes the pathological condition of the brain using mouse hippocampal neuronal HT-22 cells and adenine-induced CKD model rats. Among the uremic toxins analyzed, indoxyl sulfate, indole, 3-indoleacetate, and methylglyoxal significantly decreased viability and glutathione level in HT-22 cells. The mixture of these uremic toxins also decreased viability and glutathione level at a lower dose. Adenine-induced CKD rat showed marked renal damage, increased urinary oxidative stress markers, and increased numbers of pyknotic neuronal cells in hippocampus. CKD rats with damaged hippocampus demonstrated poor learning process when tested using the Morris water maze test. Our results suggest that uremic toxins have a toxic effect on hippocampal neuronal cells and uremic CKD rats shows pyknosis in hippocampus.

Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease.

Nicotinamide adenine dinucleotide (NAD+) supplies energy for deoxidation and anti-inflammatory reactions fostering the production of adenosine triphosphate (ATP). The kidney is an essential regulator of body fluids through the excretion of numerous metabolites. Chronic kidney disease (CKD) leads to the accumulation of uremic toxins, which induces chronic inflammation. In this study, the role of NAD+ in kidney disease was investigated through the supplementation of nicotinamide (Nam), a precursor of NAD+, to an adenine-induced CKD mouse model. Nam supplementation reduced kidney inflammation and fibrosis and, therefore, prevented the progression of kidney disease. Notably, Nam supplementation also attenuated the accumulation of glycolysis and Krebs cycle metabolites that occurs in renal failure. These effects were due to increased NAD+ supply, which accelerated NAD+-consuming metabolic pathways. Our study suggests that Nam administration may be a novel therapeutic approach for CKD prevention.

Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet.

Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade + HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade + HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade + HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients.

The effect of aldosterone on adiposity - The role of glucose absorption in the small intestine.

We have previously demonstrated that manipulation of the renin angiotensin system (RAS) has large effects on digestive efficiency. However, the effects of aldosterone on body weight, adiposity, and glucose absorption in the intestine remains unknown. We here demonstrated that lack of aldosterone synthase (ASKO) in mice did not affect adiposity. In contrast, mice administered with aldosterone were resistant to diet-induced obesity. This is due to gastrointestinal loss of dietary glucose. As expected, ASKO mice had increased glucose absorption, whereas mice administered with aldosterone had reduced glucose absorption in the small intestine. Furthermore, the level of protein expression of sodium glucose transporter 1 (SGLT1) in the mucosa of the jejunum was higher in ASKO mice, and lower in mice administered with aldosterone than control mice. Our findings indicate that aldosterone plays an important role on SGLT-1-mediated glucose absorption in the small intestine.

Protease-activated receptor 2 contributes to placental development and fetal growth in mice.

BACKGROUND: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. OBJECTIVE: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. METHODS: PAR2-/- or PAR2+/+ mice in the ICR background were used. Female PAR2-/- mice were mated with male PAR2-/- mice, and female PAR2+/+ mice were mated with male PAR2+/+ mice to obtain PAR2-/- and PAR2+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. RESULTS: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. CONCLUSION: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.

Metabolomics of a mouse model of preeclampsia induced by overexpressing soluble fms-like tyrosine kinase 1.

Preeclampsia (PE) is a leading cause of maternal morbidity and mortality. Nicotinamide has beneficial effects on PE. In this study, we evaluated the effect of nicotinamide on placental development using a PE mouse model. To generate the PE model, a recombinant adenovirus to overproduce soluble fms-like tyrosine kinase 1 (sFlt-1) was administered to mice (Jcl:ICR) at 8.5 day post-coitum (dpc). Plasma and placenta samples were harvested at 12.5 dpc. Fetal and placental weight was significantly decreased at 12.5 dpc in PE mice. Plasma and placental acylcarnitine levels were significantly higher in PE mice than those in control mice. Glycolysis was accelerated and glucose metabolic flow was altered with hypoxia, leading to ATP shortage in the labyrinth of PE mice. In PE mice, ATP production was diminished, and fatty acid oxidation was accelerated in the placenta, consequently, blood carnitine and acylcarnitine levels were increased. The mitochondrial morphology in BeWo cells was impaired under hypoxia. Nicotinamide treatment reversed fetal growth restriction, placental development, and altered metabolic flow in the early stage in PE. In addition, nicotinamide normalized impaired mitochondrial morphology. Hence, targeting this metabolic alteration in the placenta using nicotinamide may serve as a potential therapeutic approach for PE treatment.

Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease.

Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg-1·day-1), PAR2 antagonist (FSLLRY, 3 mg·kg-1·day-1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.

Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition.

In chronic kidney disease, elevated levels of circulating uremic toxins are associated with a variety of symptoms and organ dysfunction. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are microbiota-derived metabolites and representative uremic toxins. We have previously shown that the oral adsorbent AST-120 profoundly reduced pCS compared to IS in adenine-induced renal failure in mice. However, the mechanisms of the different attenuation effects of AST-120 between IS and pCS are unclear. To clarify the difference of AST-120 on IS and pCS, we investigated the levels of fecal indole and p-cresol, the respective precursors of IS and pCS, and examined the influence on the gut microbiota. Although fecal indole was detected in all groups analyzed, fecal p-cresol was not detected in AST-120 treatment groups. In genus level, a total of 23 organisms were significantly changed by renal failure or AST-120 treatment. Especially, AST-120 reduced the abundance of Erysipelotrichaceae uncultured and Clostridium sensu stricto 1, which have a gene involved in p-cresol production. Our findings suggest that, in addition to the adsorption of the uremic toxin precursors, AST-120 affects the abundance of some gut microbiota in normal and renal failure conditions, thereby explaining the different attenuation effects on IS and pCS.

Tadalafil alleviates preeclampsia and fetal growth restriction in RUPP model of preeclampsia in mice.

BACKGROUND: - Tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, alleviates preeclampsia (PE), and decreases the fetal and infant deaths associated with fetal growth restriction (FGR) in phase II clinical trial. Recently, we demonstrated that tadalafil alleviates FGR and hypertension in the dams with PE induced by l-NAME. OBJECTIVE: -The aim of present study was to clarify the effect of tadalafil in another mouse model of PE, murine reduced uterine perfusion pressure (RUPP) model we have recently developed. METHODS: -At 14.5 dpc we performed RUPP operation in mice to induce PE, administered the animals with tadalafil or vehicle in the drinking water daily from 15.5 dpc, and sacrificed them at 18.5 dpc for analyses. RESULTS: -Tadalafil improved maternal hypertension and glomerular endotheliosis in RUPP mice. Moreover, tadalafil prolonged pregnancy period, and improved survival and growth of the embryos. RUPP increased content of sFlt-1 protein in the placenta, and tadalafil corrected it back to control levels. CONCLUSION: - Tadalafil alleviates PE-like phenotype and FGR in RUPP murine model. RUPP model could help understand the mechanism of how tadalafil works on PE and FGR.

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers.

BACKGROUND: Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals. METHODS: Using a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance-spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury. RESULTS: We identified various US Food and Drug Administration-approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death. CONCLUSIONS: Although elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

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.