<scp>l</scp>‐Homocysteine‐induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia

Leng, Yiping; Ma, Yeshuo; Li, Yong; Chen, Ruifang; Zeng, Pingyu; Li, Xiaohui; Qiu, Caian; Li, Ya-Pei; Zhang, Zhen; Chen, Alex F.

doi:10.1111/bph.13920

Cited by 34 publications

(32 citation statements)

References 48 publications

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“…CTSV mediates inflammation in HUVECs by upregulating these cytokines. 92 LGALS1 binds to membrane glycoproteins, inhibiting their endocytosis and cathepsin-mediated cleavage, 93 while cathepsins induce LGALS1 in endothelial cells during angiogenesis. 94 Whether decreased expression of cathepsin targets in AMR is due to higher cleavage and higher HLA-presentation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Clotet-Freixas

McEvoy

Batruch

et al. 2020

Preprint

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Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium, which together with inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interferon gamma (IFNɣ), trigger graft injury. Unfortunately, the mechanisms governing cell-specific injury in AMR remain unclear. We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis ('non-AMR').We laser-captured and microdissected glomeruli and tubulointerstitium, and subjected them to unbiased proteome analysis. 120/2026 glomerular and 180/2399 tubulointerstitial proteins were significantly differentially expressed in AMR vs. non-AMR biopsies (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli, and CTSL, CTSS and LGMN in the tubulointerstitium. We identified galectin-1, an immunomodulatory protein upregulated in the AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells.Glutathione S-transferase omega-1 (GSTO1), an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium, and in TNFα-treated proximal tubular epithelial cells.IFNɣ and TNFα significantly increased CTSS and LGMN expression in these cells. Basement membranes are often remodeled in chronic AMR, and we demonstrated that this remodeling begins early in glomeruli and tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity. 3 SIGNIFICANCE STATEMENTAntibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss, and is caused by donor-specific antibodies against HLA antigens, which induce maladaptive responses in the kidney glomeruli and tubulointerstitium. This is the first unbiased proteomics analysis of lasercaptured/microdissected glomeruli and tubulointerstitium from 30 indication kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis. >2,000 proteins were quantified in each compartment. We discovered that basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Two ECM-modifying proteins,LGALS1 and GSTO1, were significantly increased in glomeruli and tubulointerstitium, respectively. LGALS1 and GSTO1 were upregulated by anti-HLA antibodies or AMR-related cytokines in primary kidney cells, and may represent therapeutic targets to ameliorate ECMremodeling in AMR.with gene expression alterations. 27 However, compartment-specific molecular alterations, or changes in proteome composition/expression are unknown. To address this gap, we conducted a ...

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Section: Discussionmentioning

confidence: 99%

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Clotet-Freixas

McEvoy

Batruch

et al. 2020

Preprint

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“…In the T allele carriers of the rs1801133 polymorphism, the function of MTHFR may be affected since the normal alanine residue is replaced by a valine residue in the polypeptide, which in turn affects the production of 5-MTHF and the remethylation of homcysteine, resulting in elevated plasma homosysteine levels. Studies have shown that homocysteine is a risk factor for CAD, and oxidative stress [ 33 ], vascular inflammation [ 34 ] and endothelial injury [ 35 ] are involved in the underlying mechanisms in which homocysteine causes CAD. All these events are likely to trigger the development of atherosclerosis and arterial thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis

Wang

Irfan

et al. 2018

Lipids Health Dis

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BackgroundThe associations of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) rs1801133 polymorphism with coronary artery disease (CAD) and plasma lipid levels have been widely investigated, but the results were inconsistent and inconclusive. This meta-analysis aimed to clarify the relationships of the rs1801133 polymorphism with CAD and plasma lipid levels.MethodsBy searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases, 123 studies (87,020 subjects) and 65 studies (85,554 subjects) were identified for the CAD association analysis and the lipid association analysis, respectively. Odds ratio (OR) and standardized mean difference (SMD) were used to determine the effects of the rs1801133 polymorphism on CAD risk and lipid levels, respectively.ResultsThe variant T allele of the rs1801133 polymorphism was associated with increased risk of CAD under allelic model [OR = 1.11, 95% confidence interval (CI) = 1.06–1.17, P < 0.01], additive model (OR = 1.25, 95% CI = 1.14–1.37, P < 0.01), dominant model (OR = 1.11, 95% CI = 1.04–1.17, P < 0.01), and recessive model (OR = 1.22, 95% CI = 1.12–1.32, P < 0.01). The T carriers had higher levels of total cholesterol (TC) (SMD = 0.04, 95% CI = 0.01–0.07, P = 0.02) and low-density lipoprotein cholesterol (LDL-C) (SMD = 0.07, 95% CI = 0.01–0.12, P = 0.01) than the non-carriers.ConclusionsThe meta-analysis suggested that the T allele of the rs1801133 polymorphism is a risk factor for CAD, which is possibly and partly mediated by abnormal lipid levels.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0837-y) contains supplementary material, which is available to authorized users.

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“…Homocysteine (Hcy) is a natural amino acid generated by the body’s methylation process. It is well known that hyperhomocysteinemia has become an important risk factor for cerebrovascular diseases in the general population (Leng et al, 2017 ). On the other hand, the toxic effects of Hcy on dopaminergic neurons have been confirmed in vitro and in vivo experiments (Kocer et al, 2016 ).…”

Section: Biochemical Biomarkersmentioning

confidence: 99%

Recent Advances in Biomarkers for Parkinson’s Disease

Yan

Guo

et al. 2018

Front. Aging Neurosci.

145

128

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Parkinson’s disease (PD) is one of the common progressive neurodegenerative disorders with several motor and non-motor symptoms. Most of the motor symptoms may appear at a late stage where most of the dopaminergic neurons have been already damaged. In order to provide better clinical intervention and treatment at the onset of disease, it is imperative to find accurate biomarkers for early diagnosis, including prodromal diagnosis and preclinical diagnosis. At the same time, these reliable biomarkers can also be utilized to monitor the progress of the disease. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine.

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l‐Homocysteine‐induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 34 publications

References 48 publications

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis

Recent Advances in Biomarkers for Parkinson’s Disease

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