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Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.
Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, Gewin L, Hao CM, Yang HC, Fogo AB
(2019) Nephrol Dial Transplant 34: 2042-2050
MeSH Terms: Actins, Animals, Collagen Type I, Connective Tissue Growth Factor, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Kidney Diseases, Mice, Mice, Knockout, Nerve Tissue Proteins, Serpin E2, Transforming Growth Factor beta, Ureteral Obstruction
Show Abstract · Added March 18, 2020
BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).
METHODS - Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.
RESULTS - GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.
CONCLUSION - These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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14 MeSH Terms
Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model.
Colon S, Luan H, Liu Y, Meyer C, Gewin L, Bhave G
(2019) Am J Physiol Renal Physiol 316: F360-F371
MeSH Terms: Animals, Cell Movement, Disease Models, Animal, Eosinophil Peroxidase, Eosinophils, Extracellular Matrix Proteins, Female, Fibrosis, Kidney, Male, Mice, Inbred C57BL, Mice, Knockout, Nephritis, Interstitial, Peroxidase, Peroxidases, Reactive Oxygen Species, Signal Transduction, Ureteral Obstruction
Show Abstract · Added March 26, 2019
Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (HO). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize HO into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.
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18 MeSH Terms
Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.
McCall AS, Bhave G, Pedchenko V, Hess J, Free M, Little DJ, Baker TP, Pendergraft WF, Falk RJ, Olson SW, Hudson BG
(2018) J Am Soc Nephrol 29: 2619-2625
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anti-Glomerular Basement Membrane Disease, Antibodies, Antineutrophil Cytoplasmic, Antibody Specificity, Autoantibodies, Autoantigens, Child, Cohort Studies, Collagen Type IV, Extracellular Matrix Proteins, Female, Glomerulonephritis, Hemorrhage, Humans, Lung Diseases, Male, Middle Aged, Models, Immunological, Peroxidase, Peroxidases, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP.
METHODS - We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score.
RESULTS - We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production . The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.
CONCLUSIONS - Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.
Copyright © 2018 by the American Society of Nephrology.
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In vivo Raman spectral analysis of impaired cervical remodeling in a mouse model of delayed parturition.
O'Brien CM, Herington JL, Brown N, Pence IJ, Paria BC, Slaughter JC, Reese J, Mahadevan-Jansen A
(2017) Sci Rep 7: 6835
MeSH Terms: Animals, Cervix Uteri, Cyclooxygenase 1, Extracellular Matrix Proteins, Female, Lipid Metabolism, Membrane Proteins, Mice, Nucleic Acids, Spectrum Analysis, Raman, Term Birth, Uterine Contraction
Show Abstract · Added October 11, 2017
Monitoring cervical structure and composition during pregnancy has high potential for prediction of preterm birth (PTB), a problem affecting 15 million newborns annually. We use in vivo Raman spectroscopy, a label-free, light-based method that provides a molecular fingerprint to non-invasively investigate normal and impaired cervical remodeling. Prostaglandins stimulate uterine contractions and are clinically used for cervical ripening during pregnancy. Deletion of cyclooxygenase-1 (Cox-1), an enzyme involved in production of these prostaglandins, results in delayed parturition in mice. Contrary to expectation, Cox-1 null mice displayed normal uterine contractility; therefore, this study sought to determine whether cervical changes could explain the parturition differences in Cox-1 null mice and gestation-matched wild type (WT) controls. Raman spectral changes related to extracellular matrix proteins, lipids, and nucleic acids were tracked over pregnancy and found to be significantly delayed in Cox-1 null mice at term. A cervical basis for the parturition delay was confirmed by other ex vivo tests including decreased tissue distensibility, hydration, and elevated progesterone levels in the Cox-1 null mice at term. In conclusion, in vivo Raman spectroscopy non-invasively detected abnormal remodeling in the Cox-1 null mouse, and clearly demonstrated that the cervix plays a key role in their delayed parturition.
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12 MeSH Terms
Role of Hypohalous Acids in Basement Membrane Homeostasis.
Colon S, Page-McCaw P, Bhave G
(2017) Antioxid Redox Signal 27: 839-854
MeSH Terms: Animals, Basement Membrane, Bromates, Collagen Type IV, Extracellular Matrix Proteins, Homeostasis, Oxidative Stress, Peroxidase
Show Abstract · Added March 3, 2020
SIGNIFICANCE - Basement membranes (BMs) are sheet-like structures of specialized extracellular matrix that underlie nearly all tissue cell layers including epithelial, endothelial, and muscle cells. BMs not only provide structural support but are also critical for the development, maintenance, and repair of organs. Animal heme peroxidases generate highly reactive hypohalous acids extracellularly and, therefore, target BMs for oxidative modification. Given the importance of BMs in tissue structure and function, hypohalous acid-mediated oxidative modifications of BM proteins represent a key mechanism in normal development and pathogenesis of disease. Recent Advances: Peroxidasin (PXDN), a BM-associated animal heme peroxidase, generates hypobromous acid (HOBr) to form sulfilimine cross-links within the collagen IV network of BM. These cross-links stabilize BM and are critical for animal tissue development. These findings highlight a paradoxical anabolic role for HOBr, which typically damages protein structure leading to dysfunction.
CRITICAL ISSUES - The molecular mechanism whereby PXDN uses HOBr as a reactive intermediate to cross-link collagen IV, yet avoid collateral damage to nearby BM proteins, remains unclear.
FUTURE DIRECTIONS - The exact identification and functional impact of specific hypohalous acid-mediated modifications of BM proteins need to be addressed to connect these modifications to tissue development and pathogenesis of disease. As seen with the sulfilimine cross-link of collagen IV, hypohalous acid oxidative events may be beneficial in select situations rather than uniformly deleterious. Antioxid. Redox Signal. 27, 839-854.
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MeSH Terms
The sulfilimine cross-link of collagen IV contributes to kidney tubular basement membrane stiffness.
Bhave G, Colon S, Ferrell N
(2017) Am J Physiol Renal Physiol 313: F596-F602
MeSH Terms: Animals, Basement Membrane, Biomechanical Phenomena, Collagen Type IV, Cross-Linking Reagents, Elastic Modulus, Extracellular Matrix Proteins, Genotype, Imines, Kidney, Mice, Inbred C57BL, Mice, Knockout, Peroxidase, Phenotype, Protein Conformation, Tensile Strength
Show Abstract · Added December 7, 2017
Basement membranes (BMs), a specialized form of extracellular matrix, underlie nearly all cell layers and provide structural support for tissues and interact with cell surface receptors to determine cell behavior. Both macromolecular composition and stiffness of the BM influence cell-BM interactions. Collagen IV is a major constituent of the BM that forms an extensively cross-linked oligomeric network. Its deficiency leads to BM mechanical instability, as observed with glomerular BM in Alport syndrome. These findings have led to the hypothesis that collagen IV and its cross-links determine BM stiffness. A sulfilimine bond (S = N) between a methionine sulfur and a lysine nitrogen cross-links collagen IV and is formed by the matrix enzyme peroxidasin. In peroxidasin knockout mice with reduced collagen IV sulfilimine cross-links, we find a reduction in renal tubular BM stiffness. Thus this work provides the first direct experimental evidence that collagen IV sulfilimine cross-links contribute to BM mechanical properties and provides a foundation for future work on the relationship of BM mechanics to cell function in renal disease.
Copyright © 2017 the American Physiological Society.
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16 MeSH Terms
Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV.
Colon S, Bhave G
(2016) J Biol Chem 291: 24009-24016
MeSH Terms: Basement Membrane, Collagen Type IV, Extracellular Matrix Proteins, HEK293 Cells, Humans, Peroxidase, Proprotein Convertases, Protein Domains
Show Abstract · Added March 3, 2020
The basement membrane (BM) is a form of extracellular matrix that underlies cell layers in nearly all animal tissues. Type IV collagen, a major constituent of BMs, is critical for tissue development and architecture. The enzyme peroxidasin (Pxdn), an extracellular matrix-associated protein, catalyzes the formation of structurally reinforcing sulfilimine cross-links within the collagen IV network, an event essential to basement membrane integrity. Although the catalytic function of Pxdn is known, the regulation of its activity remains unclear. In this work we show through N-terminal sequencing, pharmacologic studies, and mutational analysis that proprotein convertases (PCs) proteolytically process human Pxdn at Arg-1336, a location relatively close to its C terminus. PC processing enhances the enzymatic activity of Pxdn and facilitates the formation of sulfilimine cross-links in collagen IV. Thus, PC processing of Pxdn is a key regulatory step that contributes to its function and, therefore, supports BM integrity and homeostasis.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming.
Jones-Paris CR, Paria S, Berg T, Saus J, Bhave G, Paria BC, Hudson BG
(2017) Matrix Biol 57-58: 347-365
MeSH Terms: Animals, Basement Membrane, Collagen Type IV, Embryo Implantation, Extracellular Matrix Proteins, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Injections, Laminin, Mice, Peptide Fragments, Peroxidase, Pregnancy, Protein-Serine-Threonine Kinases, RNA, Messenger, Sesame Oil, Uterus
Show Abstract · Added October 30, 2016
Basement membranes (BMs) are specialized extracellular scaffolds that influence behaviors of cells in epithelial, endothelial, muscle, nervous, and fat tissues. Throughout development and in response to injury or disease, BMs are fine-tuned with specific protein compositions, ultrastructure, and localization. These features are modulated through implements of the BM toolkit that is comprised of collagen IV, laminin, perlecan, and nidogen. Two additional proteins, peroxidasin and Goodpasture antigen-binding protein (GPBP), have recently emerged as potential members of the toolkit. In the present study, we sought to determine whether peroxidasin and GPBP undergo dynamic regulation in the assembly of uterine tissue BMs in early pregnancy as a tractable model for dynamic adult BMs. We explored these proteins in the context of collagen IV and laminin that are known to extensively change for decidualization. Electron microscopic analyses revealed: 1) a smooth continuous layer of BM in between the epithelial and stromal layers of the preimplantation endometrium; and 2) interrupted, uneven, and progressively thickened BM within the pericellular space of the postimplantation decidua. Quantification of mRNA levels by qPCR showed changes in expression levels that were complemented by immunofluorescence localization of peroxidasin, GPBP, collagen IV, and laminin. Novel BM-associated and subcellular spatiotemporal localization patterns of the four components suggest both collective pericellular functions and distinct functions in the uterus during reprogramming for embryo implantation.
Copyright © 2016 Elsevier B.V. All rights reserved.
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18 MeSH Terms
Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension.
Wu J, Montaniel KR, Saleh MA, Xiao L, Chen W, Owens GK, Humphrey JD, Majesky MW, Paik DT, Hatzopoulos AK, Madhur MS, Harrison DG
(2016) Hypertension 67: 461-8
MeSH Terms: Animals, Aorta, Thoracic, Aortic Diseases, Cells, Cultured, Collagen, Disease Models, Animal, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Flow Cytometry, Hypertension, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Muscle, Smooth, Vascular
Show Abstract · Added February 23, 2016
Various hypertensive stimuli lead to exuberant adventitial collagen deposition in large arteries, exacerbating blood pressure elevation and end-organ damage. Collagen production is generally attributed to resident fibroblasts; however, other cells, including resident and bone marrow-derived stem cell antigen positive (Sca-1(+)) cells and endothelial and vascular smooth muscle cells, can produce collagen and contribute to vascular stiffening. Using flow cytometry and immunofluorescence, we found that adventitial Sca-1(+) progenitor cells begin to produce collagen and acquire a fibroblast-like phenotype in hypertension. We also found that bone marrow-derived cells represent more than half of the matrix-producing cells in hypertension, and that one-third of these are Sca-1(+). Cell sorting and lineage-tracing studies showed that cells of endothelial origin contribute to no more than one fourth of adventitial collagen I(+) cells, whereas those of vascular smooth muscle lineage do not contribute. Our findings indicate that Sca-1(+) progenitor cells and bone marrow-derived infiltrating fibrocytes are major sources of arterial fibrosis in hypertension. Endothelial to mesenchymal transition likely also contributes, albeit to a lesser extent and pre-existing resident fibroblasts represent a minority of aortic collagen-producing cells in hypertension. This study shows that vascular stiffening represents a complex process involving recruitment and transformation of multiple cells types that ultimately elaborate adventitial extracellular matrix.
© 2015 American Heart Association, Inc.
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16 MeSH Terms
Decellularization of intact tissue enables MALDI imaging mass spectrometry analysis of the extracellular matrix.
Gessel M, Spraggins JM, Voziyan P, Hudson BG, Caprioli RM
(2015) J Mass Spectrom 50: 1288-93
MeSH Terms: Amino Acid Sequence, Animals, Collagen, Extracellular Matrix, Extracellular Matrix Proteins, Freezing, Humans, Hydrolysis, Image Processing, Computer-Assisted, Mice, Molecular Sequence Data, Peptide Fragments, Rats, Sodium Dodecyl Sulfate, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry
Show Abstract · Added November 3, 2015
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful molecular mapping technology that offers unbiased visualization of the spatial arrangement of biomolecules in tissue. Although there has been a significant increase in the number of applications employing this technology, the extracellular matrix (ECM) has received little attention, likely because ECM proteins are mostly large, insoluble and heavily cross-linked. We have developed a new sample preparation approach to enable MALDI IMS analysis of ECM proteins in tissue. Prior to freezing and sectioning, intact tissues are decellularized by incubation in sodium dodecyl sulfate. Decellularization removes the highly abundant, soluble species that dominate a MALDI IMS spectrum while preserving the structural integrity of the ECM. In situ tryptic hydrolysis and imaging of tryptic peptides are then carried out to accommodate the large sizes of ECM proteins. This new approach allows the use of MALDI IMS for identification of spatially specific changes in ECM protein expression and modification in tissue.
Copyright © 2015 John Wiley & Sons, Ltd.
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16 MeSH Terms