Normal human glomerular basement membrane (GBM) and mesangial matrix (MM) contain several different basement membrane components in varying degrees. The characteristic morphological and ultrastructural changes in patients with diabetic nephropathy are the thickening of the GBM and the expansion of the MM. In order to investigate the changes of extracellular matrix components in diabetes, the immunohistochemical localization was performed in 17 cases with different degrees using antisera to human collagen types I, III, IV, VI, fibronectin, and laminin. The following results were obtained: 1. The reactivity for collagen IV was increased in expanded MM in the diffuse glomerulosclerosis (GS). With the progression to the nodule formation, collagen IV was prominently decreased in the peripheral area of the nodules. 2. Collagen VI was increased in GBM and MM in the diffuse GS, it was especially prominent in the expanded MM. With the progression to nodule formation, collagen VI was prominently increased in the periphery of the nodules. 3. Interstitial collagen I and III were not stained in many of the cases with the diffuse GS. With the progression to nodule formation, these were slightly expressed. A lamellar pattern of positive reaction was noted at the periphery of the late nodular lesions. 4. Fibronectin was increased in GBM & MM in the diffuse GS, it was especially intense in the MM. With the progression to the nodule formation, the reactivity of antibody to the fibronectin was decreased. 5. Laminin was weakly stained along the GBM & trace in the MM, but was not changed in the nodular GS. In summary, the expanded mesangial matrix in the diffuse GS showed a markedly increased staining for collagen IV, fibronectin and collagen VI. Less intense linear staining for collagen VI, fibronectin, laminin, collagen IV and collagen III was noted along the GBM. In the nodular GS, the composition of the early nodules resembled that of the diffuse GS. However, the late nodular lesion of the nodular GS revealed decreased reactivity for collagen IV and fibronectin at the periphery of the nodule, where collagen VI and interstitial collagen I and III were increased in laminated pattern.
Basement Membrane ; Collagen ; Diabetic Nephropathies* ; Extracellular Matrix* ; Fibronectins ; Glomerular Basement Membrane ; Humans ; Immune Sera ; Laminin

No abstract available.
Extracellular Matrix

Extracellular matrix (ECM) proteins play an important role in a series of biological processes in the cell, and their abnormal regulation can lead to many diseases. The theoretical ECM reference dataset is the basis for efficient identification of extracellular matrix proteins. Researchers have developed various ECM protein prediction tools based on machine learning methods. In this review, the main strategy of development of ECM protein prediction tools that based on machine learning methods has been introduced. Then, advances and specific characters of the existing ECM protein prediction tools have been summarized. Finally, the challenges and possible improvements of ECM protein prediction tools are discussed.
Extracellular Matrix ; Extracellular Matrix Proteins

Formation of dermal collagen fiber is a complicated and sequential process with the progressive assembly of collagen. Collagen monomers form stepped and orderly protofibrils through longitudinal displacement. Subsequently, protofibrils or protofibrils and collagen are bonded by covalent bonds to form orderly lamellar structure of collagen fibers. Then collagen fibers are tightly wound into coarse collagen fiber bundles by covalent crosslinking. Decorin is a multifunctional small leucine-rich proteoglycan. It can prevent the aggregation of protofibrils by binding to the specific site of collagen with its core protein, and adjusting the spacing between the protofibrils with its glycosaminoglycan chain. Thus, by effecting the formation of collagen fibers with regulation of collagen assembly, decorin may help prevent scar formation and even promote regeneration.
Collagen ; Decorin ; metabolism ; Extracellular Matrix ; Extracellular Matrix Proteins ; metabolism ; pharmacology ; Fibrillar Collagens ; metabolism ; ultrastructure ; Fibrin ; metabolism ; Humans ; Microfibrils ; metabolism ; Proteoglycans ; metabolism ; pharmacology

Human membranous nephropathy (MN) is morphologically characterized by subepithelial immune complex deposits and progressive thickening of glomerular basement membranes (GBM). Studies have suggested that the enhanced secretion of classical and novel type IV collagen chains in MN contributes to spike formation and the novel type IV collagen chain is particularly related to thickening of GBM. It is unclear whether the increased accumulation of extracellular matrix (ECM) proteins in GBM is due to the increased mRNA expression for type IV collagen in glomerular visceral epithelial cells (GECs). To answer this question, we analyzed seven renal biopsies of patients with idiopathic MN using in situ hybridization. In MN, the number of GECs expressing mRNA for alpha1(IV) collagen was 2.82+/-1.80/glomerular cross section (gcs), and the number expressing mRNA for alpha4(IV) collagen was 8.42+/-2.85/gcs. The number of GECs expressing mRNA for alpha4(IV) collagen was significantly larger than that of alpha1(IV) collagen mRNA. The expression of mRNA for these ECM proteins in normal controls was negligible. These results suggest that subepithelial immune complexes stimulate the gene expression of alpha1(IV) collagen and alpha4(IV) collagen in glomerular GECs which, in turn, increase the secretion of ECM proteins and contribute to the thickening of GBM in MN.
Antigen-Antibody Complex ; Biopsy ; Collagen ; Collagen Type IV* ; Extracellular Matrix ; Gene Expression ; Glomerular Basement Membrane ; Glomerulonephritis, Membranous* ; Humans* ; In Situ Hybridization ; Podocytes ; RNA, Messenger*

The hallmark of exfoliation syndrome is the appearance of white granular deposits and dandruff-like flakes on the lens,iris and angle. The incidence of glaucoma is high,and due to zonular weakening, complications are likely to occur in cataract surgery. A histopathological study with electron microscopy was performed on the iris and conjunctival tissue in order to clarify the production process of exfoliation material in the eyes with exfoliation syndrome. The materials were obtained from 13 eyes with exfoliation syndrome during surgery for glaucoma or cataract. The clumps of microfibrils were observed in the extracellular matrix, and the exfoliation materials were closely related with microfibrils.It was found that the basic unit of the exfoliation materials was microfibril. The cellular degenerations were observed in the basement membrane of capillary endothelium, especially the cells near the iris vessels. The exfoliation materials were observed around the degenerated cells; the mature or immature exfoliation materials around the iris melanocyte which show the various degrees of degeneration. The more degeneration and melting of the cells, the larger amount of exfoliation materials. This study suggests that the exfoliation materials in the eyes with exfoliation syndrome are derived from the abnormal microfibril, abnormal basement membrane, and degenerated cell itself.
Basement Membrane ; Cataract ; Endothelium, Vascular ; Exfoliation Syndrome* ; Extracellular Matrix ; Freezing ; Glaucoma ; Incidence ; Iris ; Melanocytes ; Microfibrils ; Microscopy, Electron

No abstract available.
Extracellular Matrix Proteins* ; Extracellular Matrix* ; Peptides* ; Titanium*

Diabetic nephropathy is a major cause of chronic renal failure in developing countries, and the prevalence rate has markedly increased during the past decade. Diabetic nephropathy shows various specific histological changes not only in the glomeruli but also in the tubulointerstitial region. In the early stage, the effacement of podocyte foot processes and thickened glomerular basement membrane (GBM) is noticed even at the stage of microalbuminuria. Nodular, diffuse, and exudative lesions, so-called diabetic glomerulosclerosis, are well known as glomerular lesions. Interstitial lesions also exhibit fibrosis, edema, and thickened tubular basement membrane. Diabetic nephropathy is considered to be multifactorial in origin with increasing evidence that one of the major pathways involved in the development and progression of diabetic nephropathy as a result of hyperglycemia. Hyperglycemia induces renal damage directly or through hemodynamic alterations, such as, glomerular hyperfiltration, shear stress, and microalbuminuria. Chronic hyperglycemia also induces nonhemodynamic dysregulations, such as, increased production of advanced glycosylation endproducts, oxidative stress, activation of signal pathway, and subsequent various cytokines. Those pathogenic mechanisms resulted in extracellular matrix deposition including mesangial expansion and GBM thickening, glomerular hypertrophy, inflammation, and proteinuria. In this review, recent opinions on the histopathologic changes and pathophysiologic mechanisms leading to initiation and progression of diabetic nephropathy will be introduced.
Adolescent ; Basement Membrane ; Cytokines ; Developing Countries ; Diabetic Nephropathies ; Edema ; Extracellular Matrix ; Fibrosis ; Foot ; Glomerular Basement Membrane ; Glycosylation ; Hemodynamics ; Humans ; Hyperglycemia ; Hypertrophy ; Inflammation ; Kidney Failure, Chronic ; Oxidative Stress ; Podocytes ; Prevalence ; Proteinuria ; Signal Transduction

PURPOSE: Growing data on the relationship between cytokine expression and the progression of renal diseases make these cytokines potential targets for therapeutic interventions. Weexamined the helper T1-cell- and macrophage-associated cytokines in anti-glomerular basement membrane (GBM) antibody-induced nephritis in mice and their temporal relationships with renal tissue fibrosis. METHODS: Kidneys were harvested on days 1, 3, 7, 11, and 16 after glomerulonephritis was induced with anti-GBM antibody. The progression of renal fibrosis was serially monitored to quantitate the accumulation of cortical extracellular matrix, and various cytokines were measured simultaneously. RESULTS: A single injection of anti-GBM antibody successfully produced severe crescentic glomerulonephritis. Proteinuria increased abruptly and both mesangial matrix expansion and interstitial fibrosis progressed rapidly. Cortical fibronectin and type III collagen increased continuously, reaching a peak on day 7, and the deposition of type III collagen followed the same pattern, in parallel with that of urinary transforming growth factor 1 (TGF-1) expression. Serial cytokine measurements revealed a sustained increase in interleukin (IL) 6 and monocyte chemoattractant protein 1 (MCP1) from day 3, but neither IL12, IL18, nor interferon changed significantly. Real-time polymerase chain reaction confirmed these features at the transcription level. CONCLUSION: MCP1 and IL6 correlated with the progression of renal fibrosis, with no increase in Th1- inducing cytokines. This confirms MCP1 and IL6 as attractive therapeutic targets for renal fibrosis in crescentic glomerulonephritis.
Animals ; Anti-Glomerular Basement Membrane Disease ; Autoantibodies ; Basement Membrane ; Chemokine CCL2 ; Collagen Type III ; Cytokines ; Extracellular Matrix ; Fibronectins ; Fibrosis ; Glomerulonephritis ; Interferons ; Interleukin-12 ; Interleukin-18 ; Interleukin-6 ; Interleukins ; Kidney ; Mice ; Nephritis ; Proteinuria ; Real-Time Polymerase Chain Reaction ; Transforming Growth Factors

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. METHODS: Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. RESULTS: Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. CONCLUSION: Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.
Animals ; Blood Glucose ; Blotting, Western ; Collagen Type I ; Diabetes Mellitus, Type 1 ; Diabetic Nephropathies ; Down-Regulation ; Extracellular Matrix ; Fibronectins ; Fibrosis ; Glomerular Basement Membrane ; Humans ; Mice* ; Microscopy, Electron ; Phosphorylation ; Polymerase Chain Reaction ; Rats ; Reverse Transcription ; RNA, Messenger ; Streptozocin ; Transforming Growth Factors