DOCSLIB.ORG

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-B–Induced Angiogenesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-B–Induced Angiogenesis BASIC RESEARCH www.jasn.org LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-b–Induced Angiogenesis Quan Hong,1,2 Lu Zhang,3,1 Jia Fu,1 Divya A. Verghese,1 Kinsuk Chauhan,1 Girish N. Nadkarni,1 Zhengzhe Li,1 Wenjun Ju,4 Matthias Kretzler ,4 Guang-Yan Cai,2 Xiang-Mei Chen,2 Vivette D. D’Agati,5 Steven G. Coca ,1 Detlef Schlondorff,1 John C. He,1,6 and Kyung Lee1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/activin receptor- like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes. Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes. Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression. J Am Soc Nephrol 30: ccc–ccc, 2019. doi: https://doi.org/10.1681/ASN.2018060599 Diabetic kidney disease (DKD) is a frequent compli- early stages of DKD for the design of novel preventive cation of diabetes mellitus (DM) and the most com- therapeutic strategies. mon cause of ESRD in the United States.1 Intensive glycemic control, BP control, and blockade of the renin-angiotensin-aldosterone system are the gold Received June 8, 2018. Accepted January 28, 2019. standard for current treatment of patients with Q.H. and L.Z. contributed equally to this work. 2–4 DKD. However, these established regimens pro- Published online ahead of print. Publication date available at 5 vide only partial therapeutic effects, indicating that www.jasn.org. pathogenic mechanisms driving DKD progression Correspondence: Dr. Kyung Lee or Dr. John C. He, Division of may not be targeted by current treatments. In addi- Nephrology, Mount Sinai School of Medicine, One Gustave L. tion, several recent clinical trials in DKD treatments Levy Place, New York, NY 10029. E-mail: [email protected] or were unsuccessful,5–8 highlighting an unmet need for [email protected] better understanding of mechanisms mediating the Copyright © 2019 by the American Society of Nephrology J Am Soc Nephrol 30: ccc–ccc, 2019 ISSN : 1046-6673/3004-ccc 1 BASIC RESEARCH www.jasn.org Glomerular neoangiogenesis has long been implicated as Significance Statement contributing to the morphology and pathophysiology of DKD,9–11 and dysregulated expression of various endothelial Although glomerular endothelial dysfunction and neoangiogenesis growth factors are implicated in DKD pathogenesis.12 Vascu- have long been implicated as factors contributing to diabetic kidney lar endothelial growth factor (VEGF) A is thought to contrib- disease (DKD) pathophysiology, the molecular basis of these processes is not well understood. The authors previously found fi 13 ute to the initial hyper ltration and microalbuminuria, such that a proangiogenic gene encoding leucine-rich a-2-glycoprotein 1 that blockade of VEGF signaling by pan-VEGF receptor in- (LRG1) was upregulated in isolated glomerular endothelial cells hibitor ameliorates diabetic albuminuria in mice.14 Imbalance from diabetic mice. In this work, they demonstrate in a diabetic of angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), an- mouse model that LRG1 is a novel angiogenic factor that drives DKD pathogenesis through potentiation of endothelial TGF- other family of vascular growth factors necessary for the nor- b fi /activin receptor-like kinase 1 (ALK1) signaling. They also show mal functioning of the glomerular ltration barrier, is also that plasma LRG1 is associated with renal outcome in a cohort of – implicated in altered permeability in DKD.15 17 In addition patients with type 2 diabetes. These findings indicate that LRG1 to vascular growth factors, several other mechanisms of early has a pivotal role in DKD pathogenesis through TGF-b/ALK1 glomerular endothelial cell (GEC) injury are implicated in signaling and is a risk factor for disease progression. DKD pathogenesis, such as decreased nitric oxide availabil- 18–20 21,22 ity and disturbances in endothelial barrier. These of Bambi significantly worsened diabetic glomerulopathy studies suggest that endothelial dysfunction is among the ear- in relatively DKD-resistant C57BL/6 mice, which was as- liest functional changes in diabetic kidneys. Indeed, a study by sociated with increased ALK1-mediated TGF-b signaling. 23 Weil et al. indicated that GEC injury precedes podocyte foot In an opposite manner to BAMBI, LRG1 was shown to process effacement and microalbuminuria in Pima Indians potentiate the proangiogenic ALK1 pathway by recruit- with type 2 diabetes. ment of TGF-b accessory receptor endoglin (ENG).30 Toassess the molecular changes associated with GEC injury This led us to speculate that the function of LRG1 would fi in early DKD, we recently performed transcriptomic pro ling promote diabetes-induced glomerular angiogenesis via of isolated GECs from streptozotocin (STZ)-induced diabetic ALK1-induced signal transduction in GECs. Therefore, in fi mice with endothelial nitric oxide synthase (eNOS) de - this study, we examined the role of LRG1 in diabetic glo- 24 ciency. Analysis of differentially expressed genes indeed merular injury. indicated that angiogenesis and endothelial proliferation pathways were significantly upregulated in GECs of diabetic mice,24 and that leucine-rich a-2-glycoprotein 1 (LRG1) was METHODS among the top upregulated genes. LRG1 is a secreted glyco- protein belonging to the leucine-rich repeat protein family,25 Study Approval whose expression is increased in plasma and urine of patients All mouse studies were approved by the Institutional Animal with a variety of cancer malignancies and is thought to con- Care and Use Committee at the Icahn School of Medicine at tribute to tumor-growth by promoting angiogenesis.26–29 Mount Sinai (ISMMS) and were performed in accordance with Notably, a recent finding by Wang et al.30 demonstrated that its guidelines. LRG1 mediates the proangiogenic effects through enhance- ment of TGF-b1/ALK1-mediated signaling in murine models Mouse Models of ocular disease. Mice were housed in a specific pathogen-free facility with TGF-b regulates many aspects of endothelial functions in- free access to chow and water and a 12-hour day/night cycle. 2 2 cluding cell proliferation in early diabetic kidneys resulting in Lrg1 / mouse strain in C57BL/6J background was obtained glomerular hypertrophy, but also the induction of apoptosis in from the Knock-Out Mouse Project Repository (#VG10067; microvascular endothelial cells.31 These contrasting actions of www.komp.org). Flk1-H2B-EYFP (EYFP) mice in the C57BL/6J TGF-b on endothelial cells (ECs) are regulated by differential background38 were a generous gift from Dr. Margaret Baron activation of two type 1 receptors: the ubiquitously expressed (ISMMS). Diabetes was induced with intraperitoneal injec- ALK5 and predominantly EC-restricted ALK1 receptors. tions of STZ (Sigma-Aldrich, St. Louis, MO) for five consecu- ALK5 activation induces the Smad2/3 activation to block EC tive days (50 mg/g body wt per day). To accelerate diabetic proliferation, migration, and angiogenesis; in contrast, ALK1 nephropathy, unilateral right nephrectomy was performed, as activation induces the Smad1/5/8 activation to promote described,39 3 weeks before STZ injection. Body weight and EC proliferation, migration, and tube formation, resulting fasting blood glucose levels were monitored biweekly. Diabetes in neoangiogenesis.32–36 However, the role of ALK1 in glomer- was confirmed by fasting blood glucose level .300 mg/dl. The ular angiogenesis has not been fully explored. The importance age- and sex-matched littermates injected with citrate vehicle of the TGF-b–induced ALK1 pathway in driving the DKD served as nondiabetic controls. BP was measured using the pathogenesis was shown in our recent report on BMP noninvasive tail-cuff BP system (Kent Scientific, Torrington, and Activin Membrane-Bound Inhibitor (BAMBI), a TGF-b CT). All mice were euthanized at either 12 or 20 weeks post- pseudoreceptor that represses TGF-b signaling.37 Genetic loss STZ or -vehicle injection. 2 Journal of the American Society of Nephrology J Am Soc Nephrol 30: ccc–ccc,2019 www.jasn.org BASIC RESEARCH AB 30 4 P=0.004 P<0.001 non-diabetic P<0.05 diabetic 20 2 expression P<0.001 Lrg1 mRNA (RPKM) 10 0 Lrg1 Median-centered Log2 glomerular 0 -2 Vehicle STZ DBA/2J db/db db/db;eNOS-/- C FVB WT OVE26 Neg control D In situ 4 hybridization P<0.01 3 Probes: CD31 2 LRG1 (Scores 0-4) 1 LRG1/CD31 expression 0 OVE26 FVB-WT E F HLD DKD Neg control In situ P<0.01 hybridization 4 Probe: LRG1 3 2 IF: (Scores 0-4) anti-CD31 1 DAPI LRG1/CD31 expression 0 HLD DKD Figure 1.
Load more

Recommended publications
  • LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-B–Induced Angiogenesis
    BASIC RESEARCH www.jasn.org LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-b–Induced Angiogenesis Quan Hong,1,2 Lu Zhang,3,1 Jia Fu,1 Divya A. Verghese,1 Kinsuk Chauhan,1 Girish N. Nadkarni,1 Zhengzhe Li,1 Wenjun Ju,4 Matthias Kretzler ,4 Guang-Yan Cai,2 Xiang-Mei Chen,2 Vivette D. D’Agati,5 Steven G. Coca ,1 Detlef Schlondorff,1 John C. He,1,6 and Kyung Lee1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/activin receptor- like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.
    [Show full text]
  • Analysis of Gene Expression Data for Gene Ontology
    ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins.
    [Show full text]
  • LRG1 (C-4): Sc-390920
    SANTA CRUZ BIOTECHNOLOGY, INC. LRG1 (C-4): sc-390920 BACKGROUND RECOMMENDED SUPPORT REAGENTS α LRG1 (leucine-rich 2-glycoprotein), also known as LRG, is a 347 amino acid To ensure optimal results, the following support reagents are recommended: secreted protein that contains eight LRR (leucine-rich) repeats and one LRRCT 1) Western Blotting: use m-IgGκ BP-HRP: sc-516102 or m-IgGκ BP-HRP (Cruz domain. The leucine-rich repeat (LRR) family of proteins, including LRG1, have Marker): sc-516102-CM (dilution range: 1:1000-1:10000), Cruz Marker™ been shown to be involved in protein-protein interaction, signal transduction, Molecular Weight Standards: sc-2035, UltraCruz® Blocking Reagent: cell adhesion and development. Found mainly in plasma, LRG1 is expressed sc-516214 and Western Blotting Luminol Reagent: sc-2048. 2) Immunopre- during granulocyte differentiation. The gene that encodes LRG1 consists of cipitation: use Protein A/G PLUS-Agarose: sc-2003 (0.5 ml agarose/2.0 ml). nearly 3,000 bases and maps to human chromosome 19p13.3. Chromosome 19 3) Immunofluorescence: use m-IgGκ BP-FITC: sc-516140 or m-IgGκ BP-PE: consists of over 63 million bases, houses approximately 1,400 genes and is sc-516141 (dilution range: 1:50-1:200) with UltraCruz® Mounting Medium: recognized for having the greatest gene density of the human chromosomes. sc-24941 or UltraCruz® Hard-set Mounting Medium: sc-359850. It is the genetic home for a number of immunoglobulin (Ig) superfamily mem- bers, including the killer cell and leukocyte Ig-like receptors, a number of DATA ICAMs, the CEACAM and PSG families and Fc receptors (FcRs).
    [Show full text]
  • Rabbit Anti-LRG1/FITC Conjugated Antibody
    SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-LRG1/FITC Conjugated antibody SL10536R-FITC Product Name: Anti-LRG1/FITC Chinese Name: FITC标记的富含亮氨酸α2glycoprotein抗体 1300008B03Rik; 2310031E04Rik; A2GL_HUMAN; HMFT1766; Leucine rich alpha 2 Alias: glycoprotein; Leucine-rich alpha-2-glycoprotein 1; Leucine-rich alpha-2-glycoprotein; Leucine-rich alpha-2-glycoprotein precursor; LRG; LRG1. Organism Species: Rabbit Clonality: Polyclonal React Species: Human, Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 38kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human LRG1 Lsotype: IgG Purification: affinity purified by Protein A Storage Buffer: 0.01Mwww.sunlongbiotech.com TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibody is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: The leucine-rich repeat (LRR) family of proteins, including LRG1, have been shown to be involved in protein-protein interaction, signal transduction, and cell adhesion and development. LRG1 is expressed during granulocyte differentiation (O'Donnell et al., Product Detail: 2002 [PubMed 12223515]).[supplied by OMIM, Mar 2008] Subcellular Location: Secreted. Tissue Specificity: Plasma. Similarity: Contains 8 LRR (leucine-rich) repeats.
    [Show full text]
  • ID AKI Vs Control Fold Change P Value Symbol Entrez Gene Name *In
    ID AKI vs control P value Symbol Entrez Gene Name *In case of multiple probesets per gene, one with the highest fold change was selected. Fold Change 208083_s_at 7.88 0.000932 ITGB6 integrin, beta 6 202376_at 6.12 0.000518 SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 1553575_at 5.62 0.0033 MT-ND6 NADH dehydrogenase, subunit 6 (complex I) 212768_s_at 5.50 0.000896 OLFM4 olfactomedin 4 206157_at 5.26 0.00177 PTX3 pentraxin 3, long 212531_at 4.26 0.00405 LCN2 lipocalin 2 215646_s_at 4.13 0.00408 VCAN versican 202018_s_at 4.12 0.0318 LTF lactotransferrin 203021_at 4.05 0.0129 SLPI secretory leukocyte peptidase inhibitor 222486_s_at 4.03 0.000329 ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 1552439_s_at 3.82 0.000714 MEGF11 multiple EGF-like-domains 11 210602_s_at 3.74 0.000408 CDH6 cadherin 6, type 2, K-cadherin (fetal kidney) 229947_at 3.62 0.00843 PI15 peptidase inhibitor 15 204006_s_at 3.39 0.00241 FCGR3A Fc fragment of IgG, low affinity IIIa, receptor (CD16a) 202238_s_at 3.29 0.00492 NNMT nicotinamide N-methyltransferase 202917_s_at 3.20 0.00369 S100A8 S100 calcium binding protein A8 215223_s_at 3.17 0.000516 SOD2 superoxide dismutase 2, mitochondrial 204627_s_at 3.04 0.00619 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 223217_s_at 2.99 0.00397 NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 231067_s_at 2.97 0.00681 AKAP12 A kinase (PRKA) anchor protein 12 224917_at 2.94 0.00256 VMP1/ mir-21likely ortholog
    [Show full text]
  • LRG1) As a Target for a Potential Antibody– Drug Conjugate (ADC
    University College London Appraisal of leucine-rich alpha-2-glycoprotein 1 (LRG1) as a target for a potential antibody– drug conjugate (ADC) by Faiza Javaid Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy Declaration of Authorship I, Faiza Javaid, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Faiza Javaid March 2021 i For mumma and daddy. ii Acknowledgements Bismillah, I could never have imagined that the most important undertaking of my life, and indeed the most important year of my PhD would coincide with a global pandemic. But I still maintain the conviction, Alhamdulillah, that pursuing a PhD has been the greatest (albeit the most challenging) decision I have ever made in my life, and it is in no small part due to the support and friendship of the many people I have had the fortune to meet in the process. When I think of my PhD journey, what comes to mind is not merely the untold hours of growing cells and digesting antibodies, but the sounds of AoE II, Rubiks cube contests (the Chud rites of passage - neither of which I was proficient at, but was nevertheless welcomed into the Chud fold), venturing into previously unexplored corners of YouTube (notably lemonade duck and Danny’s goodbye), that weekend in Portugal, 7 days aka the Chud anthem, numerous games of Chameleon, João’s beautiful face contagious energy and the KLB space project amongst many other interesting events.
    [Show full text]
  • Mouse Lrg1 Conditional Knockout Project (CRISPR/Cas9)-Va
    http://www.alphaknockout.com/ Mouse Lrg1 Conditional Knockout Project (CRISPR/Cas9)-vA Objective: To create a Lrg1 conditional knockout mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Lrg1 gene ( NCBI Reference Sequence: NM_029796 ; Ensembl: ENSMUSG00000037095 ) is located on mouse chromosome 17. 2 exons are identified , with the ATG start codon in exon 1 and the TGA stop codon in exon 2 (Transcript: ENSMUST00000041357). Exon 2 will be selected as conditional knockout region (cKO region). the second loxP will be inserted downstream of the TGA stop codon. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-180H19 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a knock-out allele exhibit Tgfbr1-dependent increased growth of LCC tumor allografts. The knockout of Exon 2 will result in frameshift of the gene, and covers 97.47% of the coding region. The size of intron 1 for 5'-loxP site insertion: 916 bp. The size of effective cKO region: ~1341 bp. This strategy is designed based on genetic information in existing databases. Due to the complexity of biological processes, all risk of loxP insertion on gene transcription, RNA splicing and protein translation cannot be predicted at existing technological level. The cKO region contains functional region of the Plin5 gene. Knockout the region may
    [Show full text]
  • The Plasminogen Protein Is Associated with High Myopia As
    www.nature.com/scientificreports OPEN The plasminogen protein is associated with high myopia as revealed by the iTRAQ‑based proteomic analysis of the aqueous humor Kai Wen1,3, Xianfeng Shao1,3, Yahong Li1, Yaoling Li1, Yongtao Li1, Qing Wang1, Ruihong Su1, Lujie Zhang2, Yang Cai1, Jing Sun1* & Yan Zhang1* To explore the pathogenesis of high myopia (HM) using quantitative proteomics. The aqueous humor of patients with simple nuclear cataract and nuclear cataract complicated with HM (hereinafter referred to as “C” and “HM” groups, respectively) were collected. The isobaric tags for relative and absolute quantitation (iTRAQ)‑based liquid chromatography–tandem mass spectrometry (LC– MS/MS) proteomics approach was employed to explore diferentially expressed proteins (DEPs). Bioinformatics was used to interpret the proteomic results. Furthermore, the plasminogen (PLG) protein was confrmed by enzyme‑linked immunosorbent assay (ELISA) as the candidate biomarker for HM through a receiver operating characteristic curve analysis. The study showed 32 upregulated and 26 downregulated proteins. The gene ontology analysis demonstrated that 58 DEPs corresponded to 325 biological processes, 33 cell components, and 45 molecular functional annotations. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the upregulated DEPs were highly enriched in the coagulation and complement cascades, consistent with the gene set enrichment analysis. Our data suggested that some DEPs might be hallmarks of the development of HM. ELISA confrmed that the PLG expression levels were signifcantly upregulated in HM. This was a new study investigating alterations in protein levels and afected pathways in HM using iTRAQ‑based quantitative proteomics. Our study provided a comprehensive dataset on overall protein changes and shed light on its potential molecular mechanism in human HM.
    [Show full text]
  • LRG1 Downregulation in Allergic Airway Disorders and Its Expression
    Hao et al. J Transl Med (2016) 14:202 DOI 10.1186/s12967-016-0929-2 Journal of Translational Medicine RESEARCH Open Access LRG1 downregulation in allergic airway disorders and its expression in peripheral blood and tissue cells Lijing Hao1,2†, Hua Xie3†, Bin Zhang2†, Dong Chen1, Shufen Wang1,2, Huiyun Zhang1 and Shaoheng He1* Abstract Background: Increased leucine-rich α2-glycoprotein-1 (LRG1) has been observed in plasma of individuals with vari- ous diseases. However, the role of LRG1 in allergic airway disease has not been investigated. Objective: To explore the involvement of LRG1 in allergy and its cell origins. Methods: The expression levels of LRG1 and its receptor transforming growth factor-beta receptor II (TGFBR2) in patients with allergic rhinitis (AR) and asthma (AS) were examined by flow cytometry, and enzyme-linked immuno- sorbent assay (ELISA). Results: LRG1 and soluble TGFBR2 expression in plasma of patients with AR and AS were markedly lower than that of healthy control (HC) subjects. Large proportions of CD123 HLA-DR , CD16 , CD4 , CD8 , CD14 , and CD19 cells expressed LRG1, although the percentages of LRG1 cells+ in these− cell populations+ + were lower+ in +AR and AS + patients. Up to 89.8 and 15.5 % of dispersed mast cells expressed+ LRG1 and TGFBR2. Moreover, allergen extract expo- sure significantly reduced LRG1 and TGFBR2 expression in the plasma and leukocytes of patients with AR and AS. Conclusions: Reduced LRG1 and TGFBR2 levels in patients with allergic airway disorders are likely caused by inhibi- tory actions of allergens in LRG1 producing cells. Thus, LRG1 may be a key regulatory factor of allergic responses.
    [Show full text]
  • Autocrine IFN Signaling Inducing Profibrotic Fibroblast Responses By
    Downloaded from http://www.jimmunol.org/ by guest on September 23, 2021 Inducing is online at: average * The Journal of Immunology , 11 of which you can access for free at: 2013; 191:2956-2966; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication August 2013; doi: 10.4049/jimmunol.1300376 http://www.jimmunol.org/content/191/6/2956 A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Autocrine IFN Signaling Feng Fang, Kohtaro Ooka, Xiaoyong Sun, Ruchi Shah, Swati Bhattacharyya, Jun Wei and John Varga J Immunol cites 49 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130037 6.DC1 This article http://www.jimmunol.org/content/191/6/2956.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 23, 2021. The Journal of Immunology A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling Feng Fang,* Kohtaro Ooka,* Xiaoyong Sun,† Ruchi Shah,* Swati Bhattacharyya,* Jun Wei,* and John Varga* Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN.
    [Show full text]
  • Raloxifene and N-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa
    cells Article Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa Tania Aguado 1 , Marta García 2,3,4, Adela García 2,3,4, Gemma Ferrer-Mayorga 5, Lucía Martínez-Santamaría 2,3,4 , Marcela del Río 2,3,4, Luisa-María Botella 1,* and José-María Sánchez-Puelles 1,* 1 Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, U-707 CIBERER, 28040 Madrid, Spain; [email protected] 2 Departament of Biomedical Engineering, Universidad Carlos III, 28911 Madrid, Spain; [email protected] (M.G.); [email protected] (A.G.); [email protected] (L.M.-S.); [email protected] (M.d.R.) 3 Spanish Network of Research Groups on Rare Diseases (CIBERER) U714, 28911 Madrid, Spain 4 Foundation of the Institute for Health Research, Jiménez Díaz Foundation, 28040 Madrid, Spain 5 Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain; [email protected] * Correspondence: [email protected] (L.-M.B.); [email protected] (J.-M.S.-P.); Tel.: +34-918373112 (L.-M.B.) Received: 10 August 2020; Accepted: 15 September 2020; Published: 16 September 2020 Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins.
    [Show full text]
  • Identification of Human LRG1 Polymorphisms and Their Genetic Association with Rheumatoid Arthritis
    Genomics & Informatics Vol. 6(2) 77-83, June 2008 Identification of Human LRG1 Polymorphisms and Their Genetic Association with Rheumatoid Arthritis Eun-Heui Jin1,4, Soo-Cheon Chae2*, Seung- Introduction Cheol Shim3, Hwan-Gyu Kim4 and Hun-Taeg Chung1,5* RA is a common systemic autoimmune disease that is characterized by chronic inflammation of the synovium, 1Genome Research Center for Immune Disorders, Won- which can lead to progressive joint destruction, and is kwang University School of Medicine, Iksan, Chonbuk a complex disease that is a combination of multiple ge- 570-749, Korea, 2Department of Pathology, Wonkwang netic factors and environmental contributions (Gregerin University School of Medicine, Iksan, Chonbuk 570-749, et al., 1999). RA is a disease that has a prevalence of Korea, 3Division of Rheumatology, Department of Inter- 0.3% to 1% worldwide. RA is accompanied by the nal Medicine, Eulji University School of Medicine, Dae- presence of many autoantibodies, such as rheumatoid jeon 301-831, Korea, 4Division of Biological Sciences, factors (RFs), anti-cyclic citrullinated peptide (anti-CCP) Research Center of Bioactive Materials, Chonbuk Natio- antibody, and antibodies to immunoglobulin binding pro- nal University, Chunju, Chonbuk 561-756, Korea, 5Mi- tein (BiP). RFs and anti-CCP antibody are used in clin- crobiology and Immunology, Wonkwang University ical practice (Blass et al., 1999; Schellekens et al., 2000; School of Medicine, Iksan, Chonbuk 570-749, Korea Blass et al., 2001). RFs were the first described human autoantibodies and are directed to the Fc region of IgG and are usually of the IgM isotype (Waaler et al., 1940). Abstract They are detectable in up to 10% of normal individuals Human leucine-rich alpha-2-glycoprotein 1 (LRG1) was and 70% to 80% of patients with RA, and anti-CCP can first identified as a trace protein in human serum.
    [Show full text]