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PubMed1976

The role of hydroxylation of proline in the antigenicity of basement membrane collagen.

Rabbit antibodies to bovine basement membrane collagen were used to compare the antigenic determinants of rat parietal yolk sac basement membrane [14C]procollagen with [14C]protocollagen. Basement membrane [14C]protocollagen was found to be less antigenic than basement membrane [14C]procollagen. Hydroxylation of basement membrane [14C]protocollagen, either intracellularly or in vitro with protocollagen prolyl hydroxylase, resulted in restoration of antigenicity. The difference in antigenicity observed between basement membrane [14C]procollagen and basement membrane [14C]protocollagen appeared to depend primarily upon the presence of hydroxyproline in the collagen molecule. Glucosylgalactosylhydroxylysine was found to be unimportant for antigenicity.

Animals↗
PubMed1995

Prostatic intraepithelial neoplasia and well differentiated adenocarcinoma maintain an intact basement membrane.

The status of the basement membrane in prostatic intraepithelial neoplasia (PIN) and adenocarcinoma is unsettled. Previous studies using antibodies directed against Type IV collagen have been hindered by intense staining around the stromal smooth muscle fibers, making interpretation of acinar staining difficult. We employed a monoclonal antibody to heparan sulfate proteoglycan (HSPG) to overcome this problem, recognizing that HSPG is present in the basement membrane of epithelial and endothelial cells, but not stromal smooth muscle cells. In 22 totally-embedded whole mount radical prostatectomies for adenocarcinoma which contained PIN, intense HSPG immunoreactivity was observed in the basement membrane of all normal and hyperplastic acini, 98% of acini with high grade PIN, and 100% of acini of well differentiated (Gleason score 5) adenocarcinoma; vessels served as the internal positive control, with consistent staining throughout each specimen. The extent of HSPG immunoreactivity in cancer decreased with increasing Gleason grade (measured as percent of acini staining, in 10% increments; p = 0.002). These findings indicate that HSPG is a consistent component of the basement membrane of benign, hyperplastic, and early neoplastic prostatic acini, and, unlike other extracellular matrix proteins such as type IV collagen, is not hindered by background staining around stromal smooth muscle cells. High grade PIN and well differentiated adenocarcinoma usually maintain an intact basement membrane, and loss of the basement membrane occurs with histologic dedifferentiation.

Adenocarcinoma↗
PubMed2000

Anti-angiogenic cues from vascular basement membrane collagen.

Vascular basement membrane is an important structural component of blood vessels and has been shown to interact with and modulate vascular endothelial behavior during angiogenesis. During the inductive phase of tumor angiogenesis, this membrane undergoes many degradative and structural changes and reorganizes to a native state around newly formed capillaries in the resolution phase. Such matrix changes are potentially associated with molecular modifications that include expression of matrix gene products coupled with conformational changes, which expose cryptic protein modules for interaction with the vascular endothelium. We speculate that these interactions provide important endogenous angiogenic and anti-angiogenic cues. In this report, we identify an important antiangiogenic vascular basement membrane-associated protein, the 26-kDa NC1 domain of the alpha1 chain of type IV collagen, termed arresten. Arresten was isolated from human placenta and produced as a recombinant molecule in Escherichia coli and 293 embryonic kidney cells. We demonstrate that arresten functions as an anti-angiogenic molecule by inhibiting endothelial cell proliferation, migration, tube formation, and Matrigel neovascularization. Arresten inhibits the growth of two human xenograft tumors in nude mice and the development of tumor metastases. Additionally, we show that the anti-angiogenic activity of arresten is potentially mediated via mechanisms involving cell surface proteoglycans and the alpha1beta1 integrin on endothelial cells. Collectively, our results suggest that arresten is a potent inhibitor of angiogenesis with a potential for therapeutic use.

Animals↗
PubMed1991

Embryonic lethality caused by mutations in basement membrane collagen of C. elegans.

Basement membranes are specialized forms of extracellular matrix with important functions in development. A major structural component of basement membranes is type IV collagen, a heterotrimer of two alpha 1(IV) and one alpha 2(IV) chains, which forms a complex, polygonal network associated with other basement membrane components. Here we report that the alpha 1(IV) collagen chain of Caenorhabditis elegans is encoded by the genetic locus emb-9. Mutations in emb-9 cause temperature-sensitive lethality during late embryogenesis. We have identified single nucleotide alterations that substitute glutamic acid for glycine in the triple-helical Gly-X-Y repeat region of the alpha 1(IV) collagen in three emb-9 mutant strains. These results are direct evidence that defects in basement membranes can disrupt embryonic development and form a basis for the genetic analysis of basement membrane function.

Amino Acid Sequence↗
PubMed1981

Basement membrane: structure function relationships.

Basement membranes perform several functions including filtration and elastic support. In the glomerular capillary two regions of extracellular matrix are recognized: the laminae rarae and the lamina densa. Procollagen and noncollagen glycoproteins occupy the laminae rarae and lamina densa. Proteoglycans are present in the laminae rarae. The nature and spatial organization of the macromolecules within the basement membrane determine their filtration and elastic properties. The persistence of the procollagen molecules assures the low order of fibril organization and permits selective filtration, whereas the persistence of the noncollagen extension peptides in the procollagen and the presence of the glycoprotein confers elasticity. The anionic nature of basement membranes is determined primarily by the acidic amino acid content and to much lesser extent by sialic acid and proteoglycans.

Amino Acids↗
PubMed2000

Nanoscale topography of the corneal epithelial basement membrane and Descemet's membrane of the human.

PURPOSE: Quantitatively define and compare the nanoscale topography of the corneal epithelial basement membrane (anterior basement membrane) and Descemet's membrane (posterior basement membrane) of the human. METHODS: Human corneas not suitable for transplantation were obtained from the Wisconsin Eye Bank. The corneas were placed in 2.5 mM EDTA for 2.5 h or 30 min. for removal of the epithelium or endothelium, respectively. After removal of the overlying cells, specimens were fixed in 2% glutaraldehyde and either examined in this state by atomic force microscopy only or dehydrated through an ethanol series and prepared for transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). RESULTS: The subepithelial and subendothelial basement membrane surfaces have a similar appearance that consists of an interwoven meshwork of fibers and pores. Topographic feature sizes were found to be in the nanometer size range with the epithelial basement membrane features larger and less densely packed than Descemet's membrane features. The topographic features are fractile in nature and increase surface area for cell contact. CONCLUSION: With the use of the TEM, SEM, and AFM, a detailed description of the surface topography of corneal epithelial basement membrane and Descemet's membrane of the human cornea are provided. The significance of differences in corneal basement membrane topography may reflect differences in function of the overlying cells or may be related to differences in cell migration and turnover patterns between the epithelium and endothelium.

Aged↗
PubMed1980

Preparation and histoarchitecture of ultrastructurally pure glomerular basement membrane.

Our recent morphological studies showed that basement membranes isolated from renal tubules tended to collapse and form folded sheets while glomerular basement membranes were more resilient. In an effort to study the shapes of various isolated basement membranes in undissociated tissues, a method was developed to remove all cellular elements and leave the extracellular matrix and associated basement membranes intact. Accordingly, transplant quality human kidneys were harvested, perfused with Collin's medium and transported to the laboratory on ice. The renal cortex was then peeled away by blunt dissection, further minced to 2 mm3 and placed in 1 mM EDTA (with gentle intermittent stirring) for 72 h at 4 degrees C. Solubilization of cellular materials was carried out by successive washings with 3% Triton X-100, 0.025% DNAse and 1-4% sodium deoxycholate (all with gentle stirring or shaking at 22 degrees C). Each solution contained 0.1% sodium azide. At the level of fine structure, glomerular, tubular, Bowman's capsular and peritubular capillary basement membranes all maintained their respective shapes and did not collapse. Glomerular basement membrane was particularly striking in this regard and exhibited an open, lobulated form that closely resembled its in vivo histoarchitecture. Moreover, when the acellular tissue blocks were prepared for scanning electron microscopic observation, the glomerular basement membranes exposed at the surface of the block showed a remarkable structural rigidity. These basement membranes were free-standing, convoluted electron-dense sheets, continuous with highly folded central mesangial regions. It seems significant that glomerular basement membranes maintain their in vivo conformation irrespective of the presence of other extracellular matrix components while removal of these materials by organ subfractionation results in folding and general shapelessness of tubular basement membrane. It is possible that in addition to its unique role in filtration, glomerular basement membrane may also serve to preserve glomerular shape, regardless of changing cell populations or alterations in hydrostatic pressures.

Basement Membrane↗
PubMed1980

Amyloid P-component is a constituent of normal human glomerular basement membrane.

Glomerular and other vascular basement membranes were found to contain an antigen that was immunochemically indistinguishable from serum amyloid P-component. There was no immunological cross-reactivity between antisera to serum amyloid P-component and to collagen types I, III, IV, or V. The amyloid P-component antigen was confined to the endothelial aspect, the lamina rara interna, of glomerular basement membrane. It could not be eluted by high-ionic-strength saline, EDTA, dithiothreitol, or either polar or nonpolar detergents, but was released into solution when isolated glomerular basement membrane was digested by highly purified bacterial collagenase. Most of these P-component molecules and their constituent polypeptide chains were of higher molecular weight and lower isoelectric point than serum amyloid P-component. These findings indicate that, as well as being a normal plasma protein and a universal constituent of amyloid deposits, P-component is also a normal matrix glycoprotein of basement membrane in which it is covalently linked to collagen and/or other matrix proteins. This may be relevant both to the pathogenesis of amyloidosis and to other aspects of physiology and pathology of basement membranes.

Amyloid↗
PubMed1991

Hereditary abnormalities of renal basement membranes.

The glomerular and tubular basement membranes are the principal barriers to filtration and re-absorption of water and molecules in the nephron. They are composed primarily of type IV collagen, laminin, fibronectin, sulphated proteoglycans and collagen type I. Three common inherited diseases are associated with abnormalities of basement membrane proteins: Alport's syndrome, thin basement membrane disease (TBMD) and adult polycystic kidney disease. In this review we describe the application of molecular biological techniques to the study of these conditions. Classic Alport's syndrome is an X-linked disorder with a lamellated glomerular basement membrane (GBM) which typically results in renal failure in males. Studies with sera from patients with Goodpasture's syndrome, or monoclonal antibodies specific for the Goodpasture antigen, show that the Goodpasture antigen is absent or masked in the kidneys of individuals with Alport's syndrome. There is some evidence to suggest that the Goodpasture antigen is best represented by the non-collagenous domain of the alpha 3 chain of type IV collagen, but that other non-collagenous regions may also contribute to the antigen. It is through these non-collagenous regions that the type IV collagen chains form the typical network, and the abnormality in Alport's syndrome interferes with this network formation. However, we have recently demonstrated that the gene for the non-collagenous domain of the alpha 3 collagen chain is present in individuals with Alport's syndrome. Furthermore, other groups have shown a defect in a novel type IV collagen chain, the alpha 5 chain, in 3 unrelated cases of Alport's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Basement Membrane↗
PubMed1980

Isolation of a heparan sulfate-containing proteoglycan from basement membrane.

We have isolated a unique, basement membrane proteoglycan from the Engelbreth-Holm-Swarm (EHS) sarcoma. This proteoglycan, estimated to be 0.75 X 10(6) daltons, was found to contain about equal amounts of protein and covalently linked heparan sulfate. Antibody prepared against this proteoglycan reacts with the basement membrane matrix in the tumor and with the basement membranes in skin, kidney, and cornea. These studies indicate that the heparan sulfate proteoglycan is a normal constituent of basement membranes that presumably plays an important role in the organization of basement membrane components and that also may determine the permeability of basement membranes to acidic molecules.

Amino Acids↗
PubMed1995

Role of a rat membrane inhibitor of complement in anti-basement membrane antibody-induced renal injury.

In the kidneys of anti-glomerular basement membrane (anti-GBM) antibody disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechanisms of binding of anti-GBM antibodies to TBM in vivo with special reference to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions of renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2Ag) was perfused in the left kidney and then blood circulation was restored. Mild proteinuria ( < 10 mg/16 hr) was observed during first several days. Five days later, there were tubulointerstitial injuries defined by tubular vimentin staining and leukocyte infiltration. Significant deposition of C3 was observed in the capillaries and in TBM. In rats intravenously injected with rabbit anti-rat GBM antibodies five minutes after kidney perfusion with 5I2, strong binding of rabbit IgG to TBM was observed at one and five days after injection. Although these rats showed mild proteinuria comparable to those perfused with 5I2 and those injected with normal rabbit serum, tubulointerstitial injury was significantly enhanced at Day 5. In contrast, rats perfused with irrelevant mAb and injected with anti-GBM antibodies did not show any significant binding of antibodies to TBM nor tubulointerstitial injury. Furthermore, rats which were made proteinuric by puromycin aminonucleoside and injected with anti-GBM antibodies did not show any significant binding of rabbit IgG to TBM. These results indicate that 5I2Ag, a rat membrane inhibitor of complement at the C3 convertase level, regulates vascular permeability in the living kidney, and that dysfunction or decreased expression of this molecule leads to increased accessibility of anti-GBM antibodies to TBM.

Albuminuria↗
PubMed1983

Evidence for collagen molecular orientation in basement membranes.

The following basement membranes (BMs) from representative species of the main vertebrate classes were studied by the Picrosirius-polarization method: lens capsule, Reichert's membrane and glomerular BMs. A distinct birefringence was consistently observed in all BMs from all species studied by this method. The results reported provide a strong evidence for collagen macromolecular orientation in BMs. Heparitin sulphate was the only glycosaminoglycan detected in dogs lens capsules.

Animals↗
PubMed1996

Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane.

Polymorphonuclear neutrophil (PMN) migration across basement membrane is thought to be dependent on the degradation of membrane constituents. PMN gelatinase B, a metalloproteinase able to degrade type IV collagen, may be involved in this phenomenon. PMN gelatinase B is released in the extracellular medium as a latent proform and then activated, mainly by PMN elastase. We investigated the role of gelatinase B in PMN migration across a Matrigel basement membrane matrix coated onto a filter, in a Boyden chamber. The effects of gelatinase and elastase inhibitors on PMN migration in this system were tested. Chemokinesis of PMN was tested in the same Boyden chamber across a filter free of basement membrane. The agarose method was used to test the same inhibitors for effects on PMN chemotaxis. In both systems, FMLP 10(-7)M was used as a chemoattractant. Addition of 10(-8)M TIMP-1 (the preferential gelatinase B inhibitor) inhibited trans-basement membrane PMN migration by 52 +/- 6% (P<0.05), without affecting PMN chemokinesis, chemotaxis, or degranulation. Also, (Ala)(2) Pro Val chloromethyl ketone (AAPVCK) 100 micron, a specific elastase inhibitor, inhibited trans-basement membrane PMN migration by 51 +/- 8% (P<0.05), without affecting PMN chemokinesis, chemotaxis, or degranulation. The AAPVCK-TIMP combination led to a decrease in migration across Matrigel basement membrane (46 +/- 2%, P,0.05)similar to that seen with TIMP alone. AAPVCK was responsible for inhibition of gelatinase B activation, leading to a decrease in activated gelatinase from 14% to 2% of total gelatinase release (P<0.05). All these results strongly suggest that gelatinase B is a major factor of PMN migration across basement membrane and that elastase may contribute to this process by activating pro-gelatinase B.

Amino Acid Chloromethyl Ketones↗
PubMed1984

Changes of human glomerular basement membrane in diabetes mellitus.

Glomerular basement membranes were isolated from kidneys of human diabetics and non-diabetics. Albumin and immunoglobulin G content of glomerular basement membranes as determined after protease digest was higher in the diabetic group while lower values were obtained for heparan sulphate. Nonenzymatic glucosylation of whole glomerular basement membranes and tendon tissue was significantly elevated in diabetic subjects. Correlation of the determined parameters suggest that charge and size selective properties are altered in diabetic glomeruli. Serum albumin and albumin deposited in glomerular basement membranes showed the same content of nonenzymatically bound glucose in a normal and in a diabetic subject, respectively. Thus it would appear that in human diabetes the glucosylated albumin does not underly increased transcapillary transport as was reported in vitro.

Adult↗
PubMed1989

Type VII collagen is a component of cylindroma basement membrane zone.

Cylindroma basement membranes (BMs) were studied by electron microscopy and immunofluorescence with antibodies to Types IV and VII collagen in order to correlate the ultrastructure with the biochemical characteristics. Type IV collagen served as a marker for lamina densa structures and Type VII collagen for the anchoring fibrils. Ultrastructurally, the cylindroma BMs were composed of a wide band of BM-like material in which numerous anchoring fibrils were embedded. The BMs surrounding the tumor cell clusters and nodules of BM-like material entrapped within the tumor cell islands stained positively for both Types IV and VII collagen. We conclude, that anchoring fibrils are a major component of cylindroma BM zone. A trichoepithelioma investigated as control showed a BM similar to the one found at the dermoepidermal junction, i.e. a BM distinctly different from the one of cylindroma. The trichoepithelioma BMs and nodules of BM-like material included within the tumor also stained positively for both Type IV and VII collagen.

Adult↗
PubMed1985

Isolation and characterization of a rat lung fraction enriched in alveolar wall basement membranes.

Separation of lung alveolar basement membranes from interstitial connective tissue protein has proved difficult, and a pure preparation of alveolar wall basement membranes (AWBM) is not available. We have modified a technique employing the detergent Triton X-100 for isolating AWBM from rat lungs by adding a step utilizing human skin collagenase (HSC), a highly purified enzyme obtained from skin fibroblasts that specifically cleaves non-basement membrane collagens. Triton extraction of both lungs yields 15-20 mg of basement membrane-enriched material referred to as crude fraction (CF). Ultrastructural studies show that CF includes both epithelial and endothelial basement membranes that appear similar to their in vivo counterparts and contain heparan sulfate proteoglycans. Extraction of type IV collagen is documented by the appearance of highly glycosylated hydroxylysine. This CF contains minimal amounts of contaminating elastin but significant amounts of interstitial collagens. CF was further purified for biochemical studies by incubation with HSC. HSC solubilized 20% of CF hydroxyproline resulting in a final fraction highly enriched in AWBM. Lung minces incubated in tritiated lysine produced a CF extract rich in newly formed type IV collagen, showing that lung tissue synthesizes AWBM collagen in vitro.

Animals↗
PubMed1991

Electron microscopic histochemical and immunochemical analyses of heparan sulfate proteoglycan distribution in renal glomerular basement membranes.

Renal glomerular basement membranes (GBMs) exhibit a charge-selective barrier, comprised of anionic sites, that restrict the passage of anionic molecules into the urine. These sites are located primarily in the laminae rarae interna (LRI) and externa (LRE) of the GBM and consist of heparan sulfate proteoglycan (HSPG). Previous efforts to localize HSPG core protein within various layers of the GBM have been contradictory. In the present study when rat renal cortex blocks were treated by immersion with the cationic probe, polyethyleneimine (PEI), GBMs exhibited anionic sites concentrated primarily in the LRE and more irregularly within the LRI and lamina densa. All sites were heparitinase sensitive indicating that PEI positive sites represent negatively charged groups associated with heparan sulfate. In order to gain information on the distribution of the HSPG protein core, antibodies to HSPG from the EHS tumor matrix [anti-(EHS) HSPG] and GBMs [anti-(GBM) HSPG] were used together with immunogold to label thin sections of Lowicryl embedded kidney cortex. Depending upon the antisera used, markedly different distributions of HSPG were obtained. Immunolabelling with anti-(GBM) HSPG suggested a distribution of HSPG which was restricted to the laminae rarae, whereas labelling with anti-(EHS) HSPG indicated that the protein core penetrates through all layers of the GBM.

Animals↗