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PubMed1998

Follow-up study on urinary type IV collagen in patients with early stage diabetic nephropathy.

Type IV collagen is a major component released from the glomerular and tubular basement membranes. To investigate the alteration of renal type IV collagen turnover in early stage diabetic nephropathy, urinary type IV collagen was measured by a highly sensitive one-step sandwich enzyme immunoassay (EIA). Urinary samples were obtained from 94 diabetic patients without overt proteinuria. Among those patients, 61 were normoalbuminuric and 33 patients were in the microalbuminuric group. Levels of urinary type IV collagen were serially examined at the start of this study and again one year later. The levels of urinary type IV collagen in patients in the microalbuminuric group were significantly higher than those in the normoalbuminuric group (P < 0.01). There was a significant correlation between the concentration of urinary albumin and urinary type IV collagen in both groups (P < 0.05). Twenty-eight patients (45.3%) in the normoalbuminuric group who showed an abnormal elevation of urinary type IV collagen in comparison to the reference range of normal healthy adults (normal range; less than 3.5 microg/g x Cr). Seven (25%) out of these 28 normoalbuminuric patients with increased urinary type IV collagen progressed to the microalbuminuric group one year later. The levels of urinary type IV collagen in such patients were significantly increased. In the 21 patients who stayed within the normoalbuminuric group, the urinary type IV collagen levels were significantly decreased one year later. It appears that the levels of urinary type IV collagen might reflect ongoing alteration of the extracellular matrix (ECM) turnover and might define more specifically the early stage diabetic nephropathy than the detection of microalbuminuria. It is concluded that the serial measurement of urinary type IV collagen can be a useful marker for detecting renal injury in diabetes.

Adult↗
PubMed1990

A 48 kDa collagen-binding phosphoprotein isolated from bovine aortic endothelial cells interacts with the collagenous domain, but not the globular domain, of collagen type IV.

We have identified collagen-binding proteins in detergent extracts of metabolically labelled bovine aortic endothelial cells (BAEC) by collagen type IV-Sepharose affinity chromatography. The major collagen type IV-binding protein identified by SDS/PAGE had a molecular mass of 48 kDa, which we term the 'collagen-binding 48 kDa protein' (CB48). The pI of CB48 was 8.0-8.3 in a two-dimensional gel system, running non-equilibrium pH gel electrophoresis in the first dimension and SDS/PAGE in the second dimension. Under these conditions CB48 separated into two major (a and b) and one minor isoform (c); a was the most basic of the three isoforms. Two-dimensional chymotryptic peptide maps derived from each individual isoform were virtually identical. The charge differences between the isoforms were due in part to differential H3(32)PO4 incorporation by the protein. CB48 bound to intact collagen type IV and the collagenous region of collagen type IV, but not to the globular NC1 domain. Cell-surface labelling and indirect immunofluorescence experiments localized the bulk of CB48 intracellularly in the endoplasmic reticulum Golgi region, with a minor population of molecules on the cell surface. A specific rabbit polyclonal anti-CB48 serum did not inhibit the attachment or spreading of BAEC to collagen type IV in an 'in vitro' adhesion assay, suggesting that the cell-surface population of CB48 is not involved in BAEC adhesion. We conclude that CB48 is a collagen-binding phosphoprotein that interacts with the collagenous domain of collagen type IV and may be involved in intracellular transport of collagen molecules.

Animals↗
PubMed1989

Type IV collagen synthesis by cultured mouse keratinocytes (Pam cells).

The collagens synthesized by Pam cells were biochemically characterized. The collagen in the cell layers was identified as type IV collagen by immunoprecipitation with type IV collagen specific antibody. The apparent molecular weights were 180 Kd and 175 Kd, which converted to major (160 Kd) and several minor smaller fragments with pepsin treatment. The ratios of 3-hydroxyproline/4-hydroxyproline and 4-hydroxyproline/proline in the 160 Kd polypeptide were 0.11 and 1.18, respectively. The result shows that Pam cells are able to produce type IV collagen whose biochemical characteristics are similar to those from other epithelial cells. In the kinetic study, the synthesis of type IV collagen reached its maximum level rapidly on the 1st day after seeding, suggesting that type IV collagen may play a role in cell attachment and proliferation.

Animals↗
PubMed2002

Collagen type IV in epithelial tumours of colon.

Collagen type IV in the lamina propria mucosae is one of the main components of the basement membrane of normal and transitional colon mucosa. The aim of the present study was to assess the use of anti-collagen type IV antibodies in the evaluation of biological activity of epithelial tumours of the colon. Formalin-fixed and paraffin-embedded specimens of polyps and carcinomas of the colon from 14 patients were analyzed. In transitional mucosa around epithelial tumours, only minor deformities of the evenly thick collagen type IV-containing basement membranes were found. This pattern was different in polyps where collagen type IV-positive basement membrane components extended between basolateral membranes of epithelial cells. Local changes of collagen type IV positivity in basement membranes of polyps were observed. Positivity of epithelial basement membranes disappeared in adenocarcinomas but there was an increased positivity in fibrillar components of stroma. Basement membranes of microvessels in lamina propria mucosae were also positive for collagen type IV. Similar observations were made in the stroma of polyps. Our results indicate that loss of collagen type IV in basement membranes of adenocarcinomas is related to loss of differentiation and the malignant potential of epithelial tumours of colon.

Adenocarcinoma↗
PubMed1997

Loss of type IV collagen alpha 5 and alpha 6 chains in human invasive prostate carcinomas.

Type IV collagen, a major component of basement membranes, is organized in a network responsible for the mechanical resistance of the basement membranes. It also plays a key role in epithelial cell adhesion to basement membranes. This study was designed to investigate the distribution of type IV collagen alpha-chains in normal, preneoplastic, and malignant prostate basement membranes. For this purpose, immunohistochemistry using specific antibodies raised against the different alpha-chains of type IV collagen was performed in eight normal samples, six prostatic intraepithelial neoplasia, and 20 malignant lesions of the prostate. Our results demonstrate the presence of the "novel" alpha 5 (IV) and alpha 6 (IV) chains along with the "classical" alpha 1 (IV)/alpha 2 (IV) chains in the basement membrane of the normal prostate gland. The alpha 3 (IV) chain was never detected in any prostate specimen. Prostatic intraepithelial neoplasia showed a similar immunostaining pattern to that found in normal glands. In cancer gland basement membranes, we demonstrate for the first time a specific loss of the alpha 5 (IV) and alpha 6 (IV) chains, whereas the classical alpha 1 (IV) and alpha 2 (IV) chains were consistently exhibited. Additionally, type VII collagen colocalized with alpha 5 (IV) collagen chain, and these two proteins, which were always observed in normal and prostatic intraepithelial neoplasia gland basement membranes, were lost in invasive carcinoma basement membranes. This observation raises questions about the possible association or cooperation between alpha 5 (IV)/alpha 6 (IV) chains and anchoring fibrils in prostate glands basement membrane.

Adenocarcinoma↗
PubMed1992

The alpha 4(IV) chain of basement membrane collagen. Isolation of cDNAs encoding bovine alpha 4(IV) and comparison with other type IV collagens.

Renal basement membranes are believed to contain five distinct type IV collagens. An understanding of the specific roles of these collagens and the specificities of their interactions will be aided by knowledge of their comparative structures. Genes for alpha 1(IV), alpha 2(IV), alpha 3(IV), and alpha 5(IV) have been cloned and the deduced peptide sequences compared. A fifth chain, alpha 4(IV), has been identified in glomerular and other basement membranes. Using a polymerase chain reaction-based strategy and short known peptide sequences from the noncollagenous domain (NC1), we have cloned and characterized partial bovine cDNAs of alpha 4(IV). Sequence analysis shows that this molecule has characteristic features of type IV collagens including an NH2-terminal Gly-X-Y domain which is interrupted at several points and a COOH-terminal NC1 domain with 12 cysteine residues in positions identical to those of other type IV collagens. Within the NC1 domain bovine alpha 4(IV) has 70, 59, 58, and 53% amino acid identity with human alpha 2(IV), alpha 1(IV), alpha 5(IV), and alpha 3(IV), respectively. Alignment of the peptides also shows that alpha 4(IV) is most closely related to alpha 2(IV). Nevertheless, in the extreme COOH-terminal region of the NC1 domain there are structural features that are unique to alpha 4(IV). Cloning of the region of alpha 4(IV) that encodes the NC1 domain allows comparison of all five type IV collagens and highlights certain regions that are likely to be important in the specificities of NC1-NC1 interactions and in other discriminant functions of these molecules.

Amino Acid Sequence↗
PubMed1987

Proteoglycan-19, laminin and collagen type IV production is correlated with the levels of mRNA in F9 cell aggregates differentiating in the presence or absence of cyclic AMP.

F9 embryonal carcinoma cells differentiate to embryoid bodies containing an outer epithelial layer of visceral endoderm cells when cultured as aggregates in medium containing retinoic acid (RA). Another pathway of differentiation to parietal endoderm is followed when dibutyryl cyclic AMP (cAMP) is added to the medium. We have measured the accumulated levels of RNA transcripts from a chondroitin sulfate proteoglycan gene (PG-19), the type IV collagen alpha 1, alpha 2 subunit genes, and laminin B1, B2 subunit genes during these differentiation processes. Laminin B2 gene is uniquely regulated among the extracellular matrix component genes studied. The level of laminin B2 RNA remains almost invariant during RA induction of differentiation but is induced 11-fold by cAMP with RA. In contrast, laminin B1, collagen IV alpha 1, and alpha 2 genes are induced in two stages with six- to sevenfold accumulation of RNA induced by RA and fourfold greater levels by cAMP (19- to 28-fold overall). All of these matrix-encoding genes except proteoglycan are expressed at low levels in unstimulated F9 cells, whereas PG-19 is completely undetectable and is observed only after 2 days of stimulation with RA. Its increased expression with RA and cAMP induction is at least 100-fold during F9 differentiation. Extracellular matrix transcripts are relatively stable and this accounts in part for high accumulated levels during differentiation. We conclude that several kinds of gene regulation occur among the matrix components and other differentiation markers, and this makes the F9 model system useful to study the differential effects of hormone treatments on cellular events leading to differentiation and loss of tumorigenicity.

Bucladesine↗
PubMed1987

[Collagen type IV of the basal membrane of the epithelium of the skin in certain forms of pathology].

Using immunofluorescence, attenuation or complete disappearance of type IV collagen antiserum reaction were shown in the epidermal basal membrane zone of SLE patients. Some positive material was revealed in the intercellular spaces of the epidermis. There is an inverse correlation between the amount of immune complexes in the dermo-epidermal region and the intensity of anticollagen serum reaction in the basal membrane zone. This can be explained by the toxic effect of immune complexes on collagen-synthesizing cells and the disturbance of this protein fixation in the basal membrane followed by its sequestration from the affected regions. Complex therapy including hemoperfusion restores normal collagen location in the epidermal basal membrane.

Basement Membrane↗
PubMed2002

[Fluctuation of the fibrosis markers with aging].

Actual age and biological age are not always proportional. To find out indices of aging, other than actual age, we investigated relationship between aging and four hepatic fibrosis markers: hyaluronates, type IV collagen, type IV collagen 7s and P III P. The subject of this study were 78 patients of inpatients and outpatients of our hospital. They were divided into four groups of very elderly (over 80-year-old), elderly (70-79-year-old), non-elderly (50-69-year-old), and non-elderly (20-49-year-old), and these four groups were compared. The results were as follows: regarding hyaluronates value were 86.3 +/- 46.7 ng/ml in the patients in the very elderly group, 58.9 +/- 37.4 ng/ml in the elderly group, 48.7 +/- 71.9 ng/ml in patients aged between 50 and 69 years old, and 22.6 +/- 26.1 ng/ml in patients aged between 20 and 49 years old. Regarding type IV collagen value were 134.6 +/- 27.8 ng/ml in the very elderly group, 131.1 +/- 46.5 ng/ml in the elderly group, 135.1 +/- 102.1 ng/ml in patients aged between 50 and 69 years old and 92.8 +/- 21.8 ng/ml in patients aged between 20 and 49 years old. Type IV collagen 7s value were 4.4 +/- 0.9 ng/ml in the very elderly group, 4.4 +/- 0.6 ng/ml in the elderly group, 4.8 +/- 1.6 ng/ml in patients of between 50 and 69 years old, and 4.3 +/- 0.6 ng/ml in patients between 20 and 49 years old. P III P value were 0.70 +/- 0.31 U/ml in the very elderly group, 0.64 +/- 0.34 U/ml in the elderly group, 0.59 +/- 0.43 U/ml in patients aged between 50 and 69 years old, and 0.46 +/- 0.14 U/ml in patients aged between 20 and 49 years old. The results indicated that three markers: hyaluronates, type IV collagen, P III P increased with the aging. Especially, hyaluronates were remarkably increased. Next, we studied 159 patients (78 patients added to 81 patients who visited our hospital for health checkup), and investigated the fluctuation of hyaluronate values by the aging. The results showed a definite increase of hyaluronate values with age. A correlation was recognized between ages and hyaluronate values (correlation coefficient: r = 0.64, p < 0.001). Furthermore we investigated effect on aging of various items including fibrosis markers, immunoglobulin or serum albumin by using multiple factor analysis, and found that hyaluronates influenced most strongly on aging (p < 0.0002, p < 0.00002). Thus, hyaluronates could be considered to be an index other than actual ages to evaluate progress of aging.

Adult↗
PubMed2006

Insights into early extracellular matrix evolution: spongin short chain collagen-related proteins are homologous to basement membrane type IV collagens and form a novel family widely distributed in invertebrates.

Collagens are thought to represent one of the most important molecular innovations in the metazoan line. Basement membrane type IV collagen is present in all Eumetazoa and was found in Homoscleromorpha, a sponge group with a well-organized epithelium, which may represent the first stage of tissue differentiation during animal evolution. In contrast, spongin seems to be a demosponge-specific collagenous protein, which can totally substitute an inorganic skeleton, such as in the well-known bath sponge. In the freshwater sponge Ephydatia mülleri, we previously characterized a family of short-chain collagens that are likely to be main components of spongins. Using a combination of sequence- and structure-based methods, we present evidence of remote homology between the carboxyl-terminal noncollagenous NC1 domain of spongin short-chain collagens and type IV collagen. Unexpectedly, spongin short-chain collagen-related proteins were retrieved in nonsponge animals, suggesting that a family related to spongin constitutes an evolutionary sister to the type IV collagen family. Formation of the ancestral NC1 domain and divergence of the spongin short-chain collagen-related and type IV collagen families may have occurred before the parazoan-eumetazoan split, the earliest divergence among extant animal phyla. Molecular phylogenetics based on NC1 domain sequences suggest distinct evolutionary histories for spongin short-chain collagen-related and type IV collagen families that include spongin short-chain collagen-related gene loss in the ancestors of Ecdyzosoa and of vertebrates. The fact that a majority of invertebrates encodes spongin short-chain collagen-related proteins raises the important question to the possible function of its members. Considering the importance of collagens for animal structure and substratum attachment, both families may have played crucial roles in animal diversification.

Amino Acid Sequence↗
PubMed1982

Basement membrane (type IV) collagen is a heteropolymer.

Type IV collagen was isolated in high yield from bovine kidney cortex. The protein revealed Mr = 380,000 and contained, in a 2:1 ratio, two different disulfide-linked polypeptide chains, C-1 and D-1 (Mr = 125,000). Carboxymethyl-cellulose chromatography before and after reduction proved that the two polypeptide chains are arranged in a single triple helical molecule with the chain composition (C-1)2(D-1). The disulfide bridges appear to be located 180 amino acid residues from the NH2 terminus of the chains.

Amino Acids↗
PubMed1990

A nonradioactive assay for type IV collagen degradation.

A sensitive assay for type IV collagen degradation using an avidin-biotin sandwich technique is described. Biotinylated type IV collagen is allowed to bind to an avidin-coated microtiter plate. The solution to be assayed is incubated with the biotinylated collagen bound to the avidin plate. Collagen degraded by the solution is released into the supernatant and transferred to a second plate coated with avidin. By addition of biotinylated horseradish peroxidase to this second plate, the amount of collagen degraded is determined. Our assay requires only 0.5 microgram of type IV collagen per microtiter plate and detects nanogram quantities of bacterial collagenase activity.

Animals↗
PubMed2001

Increased urinary type IV collagen marks the development of glomerular pathology in diabetic d/db mice.

The diabetic db/db mouse exhibits increased albumin excretion soon after the onset of obesity and hyperglycemia, and later manifests glomerular mesangial matrix expansion resembling that found in human diabetic nephropathy. Since the glomerular lesion in this rodent model of type 2 diabetes is associated with renal overexpression of mRNA encoding type IV collagen, we postulated that changes in the urinary excretion of collagen IV may reflect developing glomerular pathology. To explore this hypothesis, we monitored urinary collagen IV (measured by immunoassay) in db/db mice during the course of evolution of nephropathy. At age 8 weeks, collagen IV excretion was not different in diabetic compared to nondiabetic animals despite marked albuminuria, but was significantly increased in db/db compared to db/m mice at age 12 and 16 weeks. Serum levels of collagen IV did not significantly differ between normal versus diabetic mice at any age. Glomerular morphometry revealed mesangial matrix expansion at age 12 weeks, coincident with the rise in collagen IV excretion, which became more marked at age 16 weeks in association with reduced creatinine clearance and elevated serum creatinine. The findings suggest that increased urinary type IV collagen is a better indicator than albuminuria of developing glomerular matrix accumulation that results in compromised renal filtration function.

Albuminuria↗
PubMed1985

Amniotic fluid laminin and type IV collagen in normal and pathological pregnancies.

Specific radioimmunoassays for the fragment P1 of human laminin and the 7-S collagen domain of human type IV collagen were used to quantify these basement membrane proteins in second trimester amniotic fluid samples from 21 normal and 41 pathological pregnancies, the latter group being defined by elevated amniotic fluid alpha-foetoprotein (AFP) or abnormal foetal karyotype, or both. The mean laminin P1 concentration in the normal 15 to 18-wk pregnancies was 36 micrograms/l (range 10-77) and that of the 7-S collagen was 46 micrograms/l (range 7-152). The molecular size of the antigens in amniotic fluid from both normal and pathological pregnancies, when assessed by gel filtration was very large, probably representing intact laminin and type IV collagen. Pathological pregnancies, e.g. cases of Turner syndrome, Meckel syndrome and anencephaly often had elevated amniotic fluid laminin and type IV collagen concentrations. A weak, but nevertheless significant, correlation was found between the amniotic fluid laminin and type IV collagen concentrations and also between type IV collagen and AFP, but none between laminin and AFP. In eight pregnancies with foetuses suffering from the congenital nephrotic syndrome of the Finnish type, a genetic disease assumed primarily to involve some component of the glomerular basement membrane, the amniotic fluid concentrations of both laminin and type IV collagen were within normal limits in spite of an elevated amniotic fluid AFP.

Amniotic Fluid↗
PubMed1990

The spatial organization of Descemet's membrane-associated type IV collagen in the avian cornea.

The organization of type IV collagen in the unconventional basement membrane of the corneal endothelium (Descemet's membrane) was investigated in developing chicken embryos using anti-collagen mAbs. Both immunofluorescence histochemistry and immunoelectron microscopy were performed. In mature embryos (greater than 15 d of development), the type IV collagen of Descemet's membrane was present as an array of discrete aggregates of amorphous material at the interface between Descemet's membrane and the posterior corneal stroma. Immunoreactivity for type IV collagen was also observed in the posterior corneal stroma as irregular plaques of material with a morphology similar to that of the Descemet's membrane-associated aggregates. This arrangement of Descemet's membrane-associated type IV collagen developed from a subendothelial mat of type IV collagen-containing material. This mat, in which type IV collagen-specific immunoreactivity was always discontinuous, first appeared at the time a confluent endothelium was established, well before the onset of Descemet's membrane formation. Immunoelectron microscopy of mature corneas revealed that the characteristic nodal matrix of Descemet's membrane itself was unreactive for type IV collagen, but was penetrated at intervals by projections of type IV collagen-containing material. These projections frequently appeared to contact cell processes from the underlying corneal endothelium. This spatial arrangement of type IV collagen suggests that it serves to suture the corneal endothelium/Descemet's membrane to the dense interfacial matrix of the posterior stroma.

Animals↗
PubMed1993

Changes of serum 7S fragment of type IV collagen and N-terminal propeptide of type III procollagen after transcatheter arterial embolization as a model of acute liver injury.

To evaluate the mechanism of increased serum concentrations of the N-terminal propeptide of type III procollagen and the 7S fragment of type IV collagen in acute liver injury, we serially measured serum levels of these substances after transcatheter arterial embolization in patients with hepatocellular carcinoma. The results demonstrated marked increases in serum levels of the 7S fragment of type IV collagen in accordance with increased serum levels of transaminase after transcatheter arterial embolization. In contrast, a transient decrease in serum levels of the N-terminal propeptide of type III procollagen was found after transcatheter arterial embolization and transcatheter arterial infusion, although no significant changes in serum levels of the N-terminal propeptide and 7S fragment were seen after hepatic arteriography alone. The absolute change in serum levels of the 7S fragment after treatment showed positive correlation with serum transaminase levels and negative correlation with the decrease in serum levels of alpha-fetoprotein, although serum levels of N-terminal peptide did not demonstrate such a correlation. The results suggest that in acute liver injury induced by transcatheter arterial embolization, at least in part, increased in serum levels of the 7S fragment of type IV collagen reflect accelerated liberation of type IV collagen from the destroyed surrounding nontumorous tissues and that decreased serum N-terminal propeptide of type III procollagen reflects diminished synthesis of type III collagen caused by anticancer drugs.

Adult↗
PubMed2002

Crystal structure of NC1 domains. Structural basis for type IV collagen assembly in basement membranes.

Type IV collagen, which is present in all metazoan, exists as a family of six homologous alpha(IV) chains, alpha1-alpha6, in mammals. The six chains assemble into three different triple helical protomers and self-associate as three distinct networks. The network underlies all epithelia as a component of basement membranes, which play important roles in cell adhesion, growth, differentiation, tissue repair and molecular ultrafiltration. The specificity of both protomer and network assembly is governed by amino acid sequences of the C-terminal noncollagenous (NC1) domain of each chain. In this study, the structural basis for protomer and network assembly was investigated by determining the crystal structure of the ubiquitous [(alpha1)(2).alpha2](2) NC1 hexamer of bovine lens capsule basement membrane at 2.0 A resolution. The NC1 monomer folds into a novel tertiary structure. The (alpha1)(2).alpha2 trimer is organized through the unique three-dimensional domain swapping interactions. The differences in the primary sequences of the hypervariable region manifest in different secondary structures, which determine the chain specificity at the monomer-monomer interfaces. The trimer-trimer interface is stabilized by the extensive hydrophobic and hydrophilic interactions without a need for disulfide cross-linking.

Amino Acid Sequence↗
PubMed2006

Usefulness of noninvasive transient elastography for assessment of liver fibrosis stage in chronic hepatitis C.

AIM: To evaluate the method of noninvasive transient elastography for assessment of histological stage of liver fibrosis in patients with chronic hepatitis C (CHC). METHODS: Two hundred and thirty-seven patients with CHC were included in this study. Liver biopsy was performed under ultrasonography on 217 of the patients, excluding twenty with clear clinical evidence of liver cirrhosis. Fifty subjects without liver disease were enrolled as a control group (stage 0). Twenty-five patients with sustained virological response (SVR) to interferon (IFN) therapy were also enrolled. These patients underwent liver biopsy before IFN therapy. Examination of liver stiffness (LS) was performed by elastography. RESULTS: Medians (50% levels) of LS were 4.1 (3.5-4.9), 6.3 (4.8-8.5), 8.8 (6.8-12.0), 14.6 (10.5-18.6), and 22.2 (15.4-28.0), respectively, in the fibrosis stages 0-4 (P < 0.001). LS was significantly correlated with four serum fibrosis markers. LS values in patients with SVR were 3.8 (3.5-5.6), 5.2 (4.4-6.8), 6.8 (6.1-7.6), and 6.1 (3.6-7.9), respectively, in the fibrosis stages 1-4. In all stages, LS for patients with SVR was significantly lower than that for patients who did not undergo IFN therapy. LS was significantly correlated with serum concentrations of hyaluronic acid, type IV collagen, type IV collagen 7S, and type III procollagen N peptide. CONCLUSION: LS correlated well with the histological stage of fibrosis. Changes in liver fibrosis stage may thus be estimated noninvasively using transient elastography.

Adult↗