Signaling Mechanisms in the Regulation of Renal Matrix Metabolism in Diabetes

Renal hypertrophy and accumulation of extracellular matrix proteins are among cardinal manifestations of diabetic nephropathy. TGF beta system has been implicated in the pathogenesis of these manifestations. Among signaling pathways activated in the kidney in diabetes, mTOR- (mammalian target of rapamycin-)regulated pathways are pivotal in orchestrating high glucose-induced production of ECM proteins leading to functional and structural changes in the kidney culminating in adverse outcomes. Understanding signaling pathways that influence individual matrix protein expression could lead to the development of new interventional strategies. This paper will highlight some of the diverse components of the signaling network stimulated by hyperglycemia with an emphasis on extracellular matrix protein metabolism in the kidney in diabetes.

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Thromboxane stimulates synthesis of extracellular matrix proteins in vitro

AJP Renal Physiology ◽

10.1152/ajprenal.1991.261.3.f488 ◽

1991 ◽

Vol 261 (3) ◽

pp. F488-F494 ◽

Cited By ~ 5

Author(s):

L. A. Bruggeman ◽

E. A. Horigan ◽

S. Horikoshi ◽

P. E. Ray ◽

P. E. Klotman

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Mesangial Cells ◽

Extracellular Matrix Proteins ◽

Cellular Protein ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Renal Diseases ◽

Glomerular Mesangial Cells

The vasoconstrictor eicosanoid thromboxane plays an important role in the pathogenesis of several renal diseases. As an autacoid, its local release alters blood flow and induces platelet aggregation. We report a direct stimulatory effect of thromboxane on extracellular matrix protein production and gene expression in vitro. Treatment of two cell types, differentiated mouse teratocarcinoma cells (F9+) and human glomerular mesangial cells, with two different thromboxane analogues resulted in increased production of components of the extracellular matrix including fibronectin and the basement membrane proteins laminin and type IV collagen. These responses to thromboxane were not the result of a mitogenic effect of thromboxane nor the result of an increase in total cellular protein. The increased production of extracellular matrix proteins was, at least in part, due to an increase in the steady-state level of mRNA for these genes. Furthermore, the effect of thromboxane was markedly inhibited by cotreatment with a thromboxane-receptor antagonist. These results suggest a new potential role for thromboxane as a mediator of the sclerotic and fibrotic responses to injury.

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β1 integrin-extracellular matrix protein interaction modulates the migratory response to chemokine stimulation

Biochemistry and Cell Biology ◽

10.1139/o01-026 ◽

2001 ◽

Vol 79 (4) ◽

pp. 399-407 ◽

Cited By ~ 7

Author(s):

Priti S Shenoy ◽

Shashi Uniyal ◽

Kohei Miura ◽

Christopher McColl ◽

Tamas Oravecz ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Collagen Type ◽

Cell Movement ◽

Collagen Type I ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Type I ◽

Migratory Response ◽

Cc Chemokine Receptor 5

It is well established that chemokines have a major role in the stimulation of cell movement on extracellular matrix (ECM) substrates. However, it is also clear that ECM substrates may influence the ability of cells to undergo migration. Using the migration chamber method, we assessed the migratory response of human embryonic kidney-293 (HEK) transfectant cells expressing the CC chemokine receptor 5 (CCR5) (HEK-CCR5) to stimulation by chemokines (macrophage inflamatory protein (MIP)-1α, MIP-1β, and regulated on activation normal-T cell expressed and secreted (RANTES)) on ECM substrates (collagen type I and fibronectin). Using filters coated with collagen (20 µg/mL), results showed that the chemokines differed in their ability to elicit cell movement according to the order MIP-1β > RANTES [Formula: see text] MIP-1α. In contrast, using filters coated with fibronectin (20 µg/mL), all three chemokines were similar in their ability to stimulate migration of HEK-CCR5 cells. In addition, the migratory response with respect to the concentrations of ECM substrates appeared biphasic; thus, chemokine-stimulated cell movement was inhibited at high ECM concentrations (100 µg/mL). To determine the involvement of β1 integrins, results showed that the migratory response to chemokine stimulation on collagen was largely inhibited by monoclonal antibody (mAb) to α2β1; however, complete inhibition required a combination of mAbs to α1β1 and α2β1. In comparison, migration on fibronectin was inhibited by mAb to α3β1 and α5β1. Our results suggest that the migratory response to CCR5 stimulation may vary quantitatively with both the CCR5 ligand (MIP-1α, MIP-1β, and RANTES), as well as the nature and concentration of the ECM substrate involved.Key words: chemokines, integrins, cell movement, extracellular matrix proteins, CCR5.

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Self-assembling extracellular matrix proteins as materials for the condensation of silica nanostructures

RSC Advances ◽

10.1039/c6ra20911d ◽

2016 ◽

Vol 6 (97) ◽

pp. 95337-95341

Author(s):

Conor M. Gomes ◽

Leila F. Deravi

Keyword(s):

Extracellular Matrix ◽

Protein Binding ◽

Matrix Protein ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Binding Domains ◽

Synthetic Strategy ◽

Self Assembling ◽

Silica Nanostructures ◽

Biocomposite Material

A synthetic strategy is described to repurpose human extracellular matrix protein binding domains to catalyse the condensation of silica nanostructures in water for a seamlessly integrated biocomposite material.

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Localization of the Domains of the Haemophilus ducreyi Trimeric Autotransporter DsrA Involved in Serum Resistance and Binding to the Extracellular Matrix Proteins Fibronectin and Vitronectin

Infection and Immunity ◽

10.1128/iai.00819-08 ◽

2008 ◽

Vol 77 (2) ◽

pp. 657-666 ◽

Cited By ~ 31

Author(s):

Isabelle Leduc ◽

Bonnie Olsen ◽

Christopher Elkins

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Haemophilus Ducreyi ◽

Extracellular Matrix Protein ◽

Serum Resistance ◽

Passenger Domain ◽

Normal Human ◽

High Level

ABSTRACT Resisting the bactericidal activity of naturally occurring antibodies and complement of normal human serum is an important element in the evasion of innate immunity by bacteria. In the gram-negative mucosal pathogen Haemophilus ducreyi, serum resistance is mediated primarily by the trimeric autotransporter DsrA. DsrA also functions as an adhesin for the extracellular matrix proteins fibronectin and vitronectin and mediates attachment of H. ducreyi to keratinocytes. We sought to determine the domain(s) of the 236-residue DsrA protein required for serum resistance and extracellular matrix protein binding. A 140-amino-acid truncated protein containing only the C-terminal portion of the passenger domain and the entire translocator domain of DsrA exhibited binding to fibronectin and vitronectin and conferred serum resistance to an H. ducreyi serum-sensitive strain. A shorter DsrA construct consisting of only 128 amino acids was unable to bind to extracellular matrix proteins but was serum resistant. We concluded that neither fibronectin binding nor vitronectin binding is required for high-level serum resistance in H. ducreyi.

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Purification and Partial Characterization of a Paracoccidioides brasiliensis Protein with Capacity To Bind to Extracellular Matrix Proteins

Infection and Immunity ◽

10.1128/iai.73.4.2486-2495.2005 ◽

2005 ◽

Vol 73 (4) ◽

pp. 2486-2495 ◽

Cited By ~ 38

Author(s):

Angel González ◽

Beatriz L. Gómez ◽

Soraya Diez ◽

Orville Hernández ◽

Angela Restrepo ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Paracoccidioides Brasiliensis ◽

Sodium Dodecyl ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Yeast Cells ◽

Extracellular Matrix Protein ◽

Dependent Manner ◽

Fungal Propagules

ABSTRACT Microorganisms adhere to extracellular matrix proteins by means of their own surface molecules. Paracoccidioides brasiliensis conidia have been shown to be capable of interacting with extracellular matrix proteins. We aimed at determining the presence of fungal proteins that could interact with extracellular matrix protein and, if found, attempt their purification and characterization. Various extracts were prepared from P. brasiliensis mycelial and yeast cultures (total homogenates, β-mercaptoethanol, and sodium dodecyl sulfate [SDS] extracts) and analyzed by ligand affinity assays with fibronectin, fibrinogen and laminin. Two polypeptides were detected in both fungal forms. SDS extracts that interacted with all the extracellular matrix protein were tested; their molecular masses were 19 and 32 kDa. Analysis of the N-terminal amino acid sequence of the purified 32-kDa mycelial protein showed substantial homology with P. brasiliensis, Histoplasma capsulatum, and Neurospora crassa hypothetical proteins. Additionally, a monoclonal antibody (MAb) produced against this protein recognized the 32-kDa protein in the SDS extracts of both fungal forms for immunoblot. Immunofluorescence analysis revealed that this MAb reacted not only with mycelia and yeast cells, but also with conidia, indicating that this protein was shared by the three fungal propagules. By immunoelectron microscopy, this protein was detected in the cell walls and in the cytoplasm. Both the 32-kDa purified protein and MAb inhibited the adherence of conidia to the three extracellular matrix proteins in a dose-dependent manner. These findings demonstrate the presence of two polypeptides capable of interacting with extracellular matrix proteins on the surface of P. brasiliensis propagules, indicating that there may be common receptors for laminin, fibronectin, and fibrinogen. These proteins would be crucial for initial conidial adherence and perhaps also in dissemination of paracoccidioidomycosis.

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Osteoclast activity is regulated by the extracellular matrix protein fibronectin eliciting different signaling pathways

Bone ◽

10.1016/j.bone.2009.03.613 ◽

2009 ◽

Vol 44 ◽

pp. S324

Author(s):

A. Gramoun ◽

D.P. Trebec ◽

N. Azizi ◽

J. Sodek ◽

M.F. Manolson

Keyword(s):

Extracellular Matrix ◽

Signaling Pathways ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Osteoclast Activity

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Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00031.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. L687-L698 ◽

Cited By ~ 8

Author(s):

Insa Bultmann-Mellin ◽

Katharina Dinger ◽

Carolin Debuschewitz ◽

Katharina M. A. Loewe ◽

Yvonne Melcher ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Elastic Fiber ◽

Transforming Growth Factor Β ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Fiber Network

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient ( Ltbp4−/−) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4−/− lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

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Extracellular matrix protein N-glycosylation mediates immune self-tolerance in Drosophila melanogaster

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017460118 ◽

2021 ◽

Vol 118 (39) ◽

pp. e2017460118

Author(s):

Nathan T. Mortimer ◽

Mary L. Fischer ◽

Ashley L. Waring ◽

Pooja KR ◽

Balint Z. Kacsoh ◽

...

Keyword(s):

Immune Response ◽

Extracellular Matrix ◽

Matrix Protein ◽

Fat Body ◽

Extracellular Matrix Proteins ◽

Recognition System ◽

Janus Kinase ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Self Tolerance

In order to respond to infection, hosts must distinguish pathogens from their own tissues. This allows for the precise targeting of immune responses against pathogens and also ensures self-tolerance, the ability of the host to protect self tissues from immune damage. One way to maintain self-tolerance is to evolve a self signal and suppress any immune response directed at tissues that carry this signal. Here, we characterize the Drosophila tuSz1 mutant strain, which mounts an aberrant immune response against its own fat body. We demonstrate that this autoimmunity is the result of two mutations: 1) a mutation in the GCS1 gene that disrupts N-glycosylation of extracellular matrix proteins covering the fat body, and 2) a mutation in the Drosophila Janus Kinase ortholog that causes precocious activation of hemocytes. Our data indicate that N-glycans attached to extracellular matrix proteins serve as a self signal and that activated hemocytes attack tissues lacking this signal. The simplicity of this invertebrate self-recognition system and the ubiquity of its constituent parts suggests it may have functional homologs across animals.

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β1 integrins are distributed in adhesion structures with fibronectin and caveolin and in coated pits

Biochemistry and Cell Biology ◽

10.1139/o03-063 ◽

2003 ◽

Vol 81 (5) ◽

pp. 335-348 ◽

Cited By ~ 9

Author(s):

Nikhat D Boyd ◽

Bosco M. C Chan ◽

Nils O Petersen

Keyword(s):

Extracellular Matrix ◽

Protein Kinase ◽

Matrix Protein ◽

Adaptor Protein ◽

Cytoskeletal Proteins ◽

Matrix Proteins ◽

Mitogen Activated Protein Kinase ◽

Extracellular Matrix Protein ◽

Coated Pits ◽

Mitogen Activated Protein

Integrins are found in adhesion structures, which link the extracelullar matrix to cytoskeletal proteins. Here, we attempt to further define the distribution of β1 integrins in the context of their association with matrix proteins and other cell surface molecules relevant to the endocytic process. We find that β1 integrins colocalize with fibronectin in fibrillar adhesion structures. A fraction of caveolin is also organized along these adhesion structures. The extracellular matrix protein laminin is not concentrated in these structures. The α4β1 integrin exhibits a distinct distribution from other β1 integrins after cells have adhered for 1 h to extracellular matrix proteins but is localized in adhesion structures after 24 h of adhesion. There are differences between the fibronectin receptors: α5β1 integrins colocalize with adaptor protein-2 in coated pits, while α4β1 integrins do not. This parallels our earlier observation that of the two laminin receptors, α1β1 and α6β1, only αaβ1 integrins colocalize with adaptor protein-2 in coated pits. Calcium chelation or inhibition of mitogen-activated protein kinase kinase, protein kinase C, or src did not affect localization of α1β1 and α5β1 integrins in coated pits. Likewise, the integrity of coated-pit structures or adhesion structures is not required for integrin and adaptor protein-2 colocalization. This suggests a robust and possibly constitutive interaction between these integrins and coated pits.Key words: adhesion, endocytosis, extracellular matrix, microscopy, confocal, signalling.

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