Glomerular Basement Membrane Disorders in Experimental Models for Renal Diseases: Impact on Understanding Pathogenesis and Improving Diagnosis
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Animal models have provided important insights into human renal diseases that arise from mutations in genes that encode or regulate the synthesis of glomerular basement membrane proteins. This chapter describes several well-characterized animal models of type IV collagen disorders (Alport syndrome, HANAC syndrome), a laminin disorder (Pierson syndrome), nail-patella syndrome and HERNS syndrome. These models can be exploited in studies of the pathogenesis and treatment of such disorders.Keywords:
Alport syndrome
Pathogenesis
Type IV collagen
Normal human oral mucosa (20 biopsies) and similar tissue transplanted to nude mice (44 transplants) were investigated for the presence of laminin and type IV collagen, using an indirect immunofluorescence staining technique. Laminin and type IV collagen were consistently found in the basement membrane area of the epithelial-stromal junction, and of the vessels of both normal oral mucosa and oral mucosal transplants. De novo synthesis of laminin and type IV collagen by transplanted epithelium was evidenced by the finding of an increased thickness of basement membrane deposits. New basement membrane-like material was also seen between the migrating human epithelial cells and the murine connective tissue. By application of species-specific monoclonal antibodies to human laminin and type IV collagen, it was demonstrated that human epithelial cells have the ability to participate in the information of their basement membranes. The use of both species-specific and species-unspecific antibodies showed that the vessel supply of the transplants was of both human and murine origin.
Type IV collagen
Oral mucosa
Immunofluorescence
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Type IV collagen
Dermoepidermal junction
Skin equivalent
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Immunocytochemical stains for laminin and type IV collagen can be used as markers for basement membrane and vascular endothelium.Thirty four follicular thyroid lesions were examined using these techniques to investigate two aspects: firstly, the relation between the extent of invasion and the integrity of basement membrane; secondly, whether the techniques could enhance the detection of tumour vascular invasion.The results showed that although basement membrane was lost in widely invasive tumours, preservation was seen in most but not all encapsulated tumours.The potential for improved recognition of vascular invasion was also found.
Type IV collagen
Vascular invasion
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Immunofluorescent distribution of basement membrane components laminin and collagen type IV was studied in 51 rat colon tumors induced by 1, 2-dimethylhydrazine. In normal colonic mucosa, adenomas and carcinomas in situ continuous basement membranes were present, while in adenocarcinomas they were altered to different extents. An uncoordinated loss, or dissociation, of the two markers studied was found: the degree of collagen type IV loss was often much higher than that of laminin in the same tumor. These data suggest that a reliable determination of cancer invasion by monitoring basement membrane alteration requires the use of several basement membrane markers.
1,2-Dimethylhydrazine
Type IV collagen
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Alport syndrome
Type IV collagen
Glomerulus
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Distribution of type IV collagen and laminin in the gingival capillary basement membrane from streptozotocin-induced diabetic rats was investigated using immunoelectron microscopy. Both type IV collagen and laminin were found throughout the basement membrane. Quantitative analysis revealed that the immunoreactive area for laminin did not change with age, and the width of laminin deposition remained constant, even when diabetes was induced in the animals. However, the immunoreactive area for type IV collagen thickened with age. Further, the width of type IV collagen in the basement membrane increased markedly 36 weeks after diabetes was induced. It was concluded that the thickening of the gingival capillary basement membrane in experimentally induced diabetic rats was due an increase of type IV collagen deposition.
Type IV collagen
Immunoelectron microscopy
Lamina densa
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Abstract. Kidneys from mice, dogs, and humans with X-linked and autosomal-recessive forms of Alport syndrome were examined by immunofluorescence for expression of laminin α, β, and γ chains using monospecific antibodies. Laminin α2 chain was absent from glomerular basement membranes (GBM) in normal human, murine, and canine kidneys but was abnormally deposited in Alport GBM, regardless of species or inheritance pattern. In murine and canine Alport kidneys, laminin α2 seems to be deposited as part of both laminin-2 (α2β1γ1) and laminin-4 (α2β2γ1) but as part of only laminin-4 in human Alport kidneys. GBM laminin α2 chain deposition was not observed in a variety of non-Alport human glomerulopathies. This finding adds to the list of proteins that are aberrantly deposited in Alport GBM as a consequence of the absence of the α3, α4, and α5 chains of type IV collagen: ( 1 ) type IV collagen α1 and α2 chains, ( 2 ) type V collagen, ( 3 ) type VI collagen, and most recently ( 4 ) the laminin α2 chain and ( 5 ) the laminin α1 and β1 chains in mice and dogs. These findings emphasize further the critical role played by the α3, α4, and α5 chains of type IV collagen in establishing and maintaining the composition, structure, and function of mature GBM.
Alport syndrome
Type IV collagen
Immunofluorescence
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Human carcinomas of the pancreas are aggressive tumors which traverse basement membrane barriers during invasion and metastasis. In order to examine the relationship of pancreatic tumor cells to basement membranes, we analyzed and compared the capabilities of four biologically different human pancreatic adenocarcinoma lines to adhere to substrate coated with purified basement membrane constituents. Each of the four cell lines adhered readily to purified laminin in a dose-dependent manner, although differences were noted in the time required for optimum attachment. Significant variations in the abilities of the cell lines to attach to purified fibronectin were evident both in concentration dependence and in the time required for attachment and spreading. Adhesion to type IV collagen was negligible for two of the four tumor lines but addition of soluble laminin or fibronectin augmented attachment. The other two cell lines attached only moderately to type IV collagen and this attachment was not enhanced by soluble laminin or fibronectin. When laminin or fibronectin was coated directly over type IV collagen, attachment of all four cell lines was comparable to that for the glycoproteins alone. Although the tumor lines were all established from human neoplasms of similar histological origin and retained the ability to adhere to intact basement membranes prepared from human amnion, they exhibited various patterns of attachment to laminin, fibronectin, and type IV collagen.
Type IV collagen
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The developmental localization patterns of collagen type IV alpha1-5 chains, laminin-1, laminin-5, and laminin alpha2 chain were analyzed in the embryonic mouse eye using isoform specific antibodies and immunofluorescence microscopy. Laminin-1 isoform and alpha1-2(IV) were ubiquitously expressed along the ocular surface basement membranes at a very early stage of eye development. Alpha3-5(IV) were first detected at later stages of development, and exhibited a variable distribution pattern along the ocular surface basement membrane. In contrast, expression of the laminin alpha2 chain was restricted to the conjunctival basement membrane, and was first detected during the same developmental period in which keratin K4-positive, differentiated conjunctival epithelial cells were observed. Although laminin-5 was uniformly expressed along the adult ocular surface basement membrane, during embryogenesis it was first incorporated into the conjunctival basement membrane structure. These data suggest that some of the laminin isoforms, including laminin alpha2 and laminin-5, may play a role in the formation of a conjunctival-type basement membrane. The temporal relationship between the localization of these molecules to the conjunctival basement membrane and the appearance of differentiated conjunctival epithelial cells suggests a role for external influence on the differentiation pathways of ocular surface epithelium.
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