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1.
ICR-derived strain with glomerulonephritis (ICGN) is a strain of mice with hereditary nephrotic syndrome with an unidentified cause. Based on histopathological and biochemical data, ICGN mice are considered to be a good experimental model for human idiopathic nephrotic syndrome. In the present study, we histochemically investigated the changes in localization of extracellular matrix (ECM) components and transforming growth factor beta1 (TGF-beta1). Strong immunohistochemical staining of basal membrane ECM components (collagen IV and laminin) and interstitial ECM components (type III collagen and fibronectin) were demonstrated in glomeruli and tubulointerstitum of ICGN mice as compared with those of sex and age-matched ICR mice, used as normal healthy controls. Marked type I collagen and tenascin deposition, which were not detected in the glomeruli of ICR mice, were seen in the glomeruli of ICGN mice. A remarkable increase in active-TGF-beta1 was also detected only in glomeruli of ICGN mice, but not in those of ICR mice. Furthermore, strikingly increased alpha-smooth muscle actin, a marker of activated glomerular mesangial cells, was demonstrated in the glomeruli, mainly in the mesangial cells, of ICGN mice. These findings indicated that ECM components are increased in the glomerulus and tubulointerstitum of ICGN mice, and that active-TGF-beta1 induces such increases in ECM components. The present findings may contribute to elucidation of the pathogenic mechanisms of hereditary nephrotic syndrome in ICGN mice and, in future, human idiopathic nephrotic syndrome.  相似文献   

2.
Matrix metalloporoteinases (MMPs), which are dominantly regulated by tissue inhibitors of metalloproteinase (TIMPs), play important roles in extracellular matrix (ECM) degradation and are involved in the progression of kidney diseases. In glomeruli and tubulointerstitum of hereditary nephrotic (ICR-derived glomerulonephritis: ICGN) mouse kidneys, hyper-accumulation of ECM components occurred, and MMP activity decreased. In the present study, because lower levels of MMP activity may contribute to the progression of renal fibrosis in ICGN mice, Western blotting analysis and immunohistochemical staining for MMPs and TIMPs were performed to verify the expression levels of these proteins. Levels of MMP-2, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 in the kidneys were decreased in ICGN mice in comparison with normal ICR mice. These results indicate that small amounts and low levels of activity of MMPs cause the progression of renal fibrosis in ICGN mice.  相似文献   

3.
Renal fibrotic change, extreme accumulation of extracellular matrix (ECM) components in glomeruli and tubulointerstitum, is one of the characteristic features of ICR-derived glomerulonephritis (ICGN) mice. Decreased degradation of ECMs by matrixmetalloproteinases was demonstrated in kidneys of ICGN mice. To determine the balance between production and degradation of ECMs in kidneys of ICGN mice, we examined expression of mRNAs of ECMs in those. To demonstrate the localization of type I, III and IV collagen mRNAs in kidney sections of ICGN and control ICR mice, in situ hybridization using digoxigenin-labeled oligonucleotide antisense probes for procollagen-alpha(1) (I), -alpha(1) (III) and -alpha(1) (IV) mRNAs, respectively, was performed. Negative or trace expressions of type I and III collagen mRNAs were observed in the kidneys of control mice, but stronger expressions of those were seen in glomeruli and injured renal tubules of the kidneys of ICGN mice. Moderate expression of type IV collagen mRNA was demonstrated in a part of glomeruli and renal tubules of both control and ICGN mice, and no remarkable difference was seen between them. Severe renal fibrosis, extreme accumulation of interstitial type I and III collagens is caused by increased production and decreased degradation in the kidneys of ICGN mice. Thus, the profiles of metabolism between interstitial and membranous collagens may be different in the kidneys of ICGN mice, and excessive production of interstitial collagens may be the dominant cause of renal disease in them.  相似文献   

4.
The ICR-derived glomerulonephritis (ICGN) mouse is a novel inbred mouse strain with a hereditary nephrotic syndrome, considered to be a good model of human idiopathic nephrotic syndrome and develops proteinuria, hypoproteinemia and anemia. In the present study, we compared the cell kinetics in the kidneys of ICGN mice with age-matched ICR mice as normal controls. The proliferating cells were visualized by 5-bromo-2'-deoxyuridine labeling, and apoptotic cells were determined by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling. Many proliferating epithelial cells of renal tubules, glomerular mesangial cells and tublointerstitial fibroblast-like cells were observed in the kidneys of ICGN mice, but no proliferating cells were seen in the kidneys of ICR mice. Apoptotic cells had round nuclei, and were observed only in the tubulointerstitium in the kidneys of ICGN mice but not in that of controls. The proliferation of renal tubular epithelial cells may represent a compensatory response, and that of mesangial and fibroblast-like cells may play a pathogenic role in nephrotic syndrome. Apoptosis in tubulointerstitial cells with round nuclei may have been erythropoietin-producing cells, and probably caused anemia.  相似文献   

5.
The ICR-derived glomerulonephritis (ICGN) mice consist of heterozygous and homozygous groups and are considered to be a good model for human idiopathic nephrotic syndrome. To reveal changes in cell-surface carbohydrate construction, 24 lectins were applied to kidney sections of 10-, 30- and 50-week-old male heterozygous and homozygous ICGN mice and age-matched male ICR mice. Bandeiraea simplicifolia lectin-I (BSL-I), which specifically binds to alpha-D-galactopyranosyl groups, showed positive staining in the glomeruli of ICGN mice, but not in those of ICR mice. Positive BSL-I staining was observed only in distal tubules of homozygous ICGN mice. Lectin blotting for BSL-I demonstrated characteristic glycoproteins (45, 58 and 64 kD) in ICGN but not in ICR mice, and the levels of these molecules augmented in homozygous ICGN mice with the progression of renal failure. Moreover, succinylated wheat germ agglutinin, Dolichos biflorus agglutinin, Aleuria aurantia lectin and Ulex europaeus agglutinin-I showed positive staining only in the glomeruli of homozygous ICGN mice, but not in those of heterozygous ICGN or ICR mice. The staining intensities of Ricinus communis agglutinin-I, Phaseolus vulgaris agglutinin-E and -L, Lens culinaris agglutinin and Erythrina cristagalli agglutinin (ECL) in the glomeruli of homozygous ICGN mice were stronger than those of heterozygous ICGN and ICR mice. In conclusion, lectin histochemistry provided useful information for the diagnosis and prognosis of nephrotic lesions. Characteristic BSL-I binding glycoproteins may be pathogenic factors which cause renal disease in ICGN mice and are good tools to investigate the molecular mechanism of renal disorders in ICGN mice.  相似文献   

6.
Anemia is a major secondary symptom in chronic renal disorder (CRD), but the precise cause of insufficient production of erythropoietin (EPO) remains unclear owing to the controversial localization of EPO-producing cells in the kidneys. The ICR-derived glomerulonephritis (ICGN) mouse, a new hereditary nephrotic mouse, is an appropriate model of anemia associated with CRD. By using an amplified in situ hybridization technique, we detected and counted the renal EPO-producing cells under both normoxic and hypoxic conditions. The expression levels of renal EPO mRNA were quantified and oxygen gradients were also assessed immunohistochemically. Amplified in situ hybridization clarified that EPO-producing cells were peritubular interstitial cells in the middle region of renal cortex in both ICR and ICGN mice. Hypoxia (7% O2) induced low oxygen tension in proximal tubular epithelial cells of renal cortex, and increased the expression of EPO mRNA and the number of EPO-producing cells in both ICR and ICGN mice. However, hypoxia did not increase the serum EPO levels in ICGN mice. The ICGN mouse is a good model for anemia associated with CRD, and the suppression of EPO protein production in the renal EPO-producing cells is considered to be a potential cause of anemia associated with CRD.  相似文献   

7.
The ICR-derived glomerulonephritis (ICGN) mouse, a novel inbred mouse strain with a hereditary nephrotic syndrome, develops severe anemia associated with chronic renal failure. To reveal the pathogenic mechanism of anemia in ICGN mice, we subcutaneously administered recombinant human erythropoietin (rhEPO; 5 IU/mouse/day) or saline for 5 days to ICGN mice. In terminal-stage ICGN mice with severe anemia, rhEPO significantly increased hematocrit (Ht), red blood cells (RBC) and hemoglobin levels. Endogenous EPO levels in peripheral blood were reduced by rhEPO injection. No histopathological changes in bone marrow and kidneys were induced by rhEPO injection. Insufficiency of EPO may cause anemia in ICGN mice.  相似文献   

8.
The ICR-derived glomerulonephritis (ICGN) mouse, a new inbred mouse strain with a hereditary nephrotic syndrome, is considered to be a good model of human idiopathic nephrotic syndrome and notably exhibits proteinuria and hypoproteinemia from the neonatal stage. In chronic renal disorder (CRD), anemia is a major subsequent symptom (renal anemia). The precise cause of renal anemia remains unclear, primarily owing to the lack of appropriate spontaneous animal models for CRD. To establish adequate animal models for anemia with CRD, we examined the hematological-biochemical properties and histopathological characteristics. With the deterioration of renal function, ICGN mice developed a normochromic and normocytic anemia, and exhibited normochromic and microcytic at the terminal stage. The expression of erythropoietin (EPO) mRNA both in the kidneys and liver and the EPO leak into the urine were observed in ICGN mice, indicating a disrupted metabolism of EPO in ICGN mice. In addition, a lack of iron induced by the hemolysis in the spleen and the leak of transferrin into urine as proteinuria aggravated the anemic condition. In conclusion, the ICGN mouse is a good model for anemia with CRD.  相似文献   

9.
Nivalenol (NIV) is a trichothecene mycotoxin produced by Fusarium fungi that frequently contaminates agricultural commodities. Dietary administration of NIV to adult mice affects the renal glomeruli, but data about NIV toxicity in human infants are limited. To evaluate the effects of NIV on infant kidneys, 3-week-old male ICR-derived glomerulonephritis (ICGN) and ICR mice were administered 0, 4, 8 or 16 ppm NIV in diet for 4 weeks, and their renal status was compared with age-matched or adult ICR mice. In ICGN mice, the number of glomeruli showing mesangial expansion and α-smooth muscle actin (SMA)-positive mesangial cells was higher with 16 ppm NIV compared with controls. No other significant differences were observed in ICGN mice. In infant ICR mice, the IgA serum concentrations were significantly elevated without glomerular morphological changes in the 16 ppm NIV group. There was no difference in NIV sensitivity in the kidneys of infant ICGN and ICR mice. These data suggest that the kidneys in infant mice are not sensitive to nivalenol under the present conditions.  相似文献   

10.
The interactions of tumor cells with the extracellular matrix (ECM) are a crucial step in invasion and metastasis. Integrins are adhesive molecules forming heterodimers with alpha and beta subunits that play a definitive role in these interactions. In this study, mastocytoma (mast cell tumor: MCT) cell-ECM interaction was investigated using 3 canine MCT cell lines: CM-MC (originating from cutaneous MCT), VI-MC (originating from intestinal MCT), and CoMS (originating from oral MCT). Flow cytometric analysis showed that all cells highly expressed the integrin beta1 and alpha1 through alpha5 subunits and that they moderately expressed the alpha6 subunit. In adhesion studies, CoMS weakly but spontaneously adhered to fibronectin (FN), which was enhanced by phorbol ester (TPA), while CM-MC and VI-MC required cell activation by TPA to adhere to FN. Anti-beta1 and alpha5 integrin antibodies strongly inhibited cell adhesion to FN in CM-MC and CoMS and moderately inhibited cell adhesion in VI-MC. Only VI-MC adhered to laminin (LN) under activation by TPA. Anti-beta1 integrin antibodies strongly inhibited cell adhesion to LN, but all anti-alpha integrin antibodies failed to inhibit cell adhesion to LN. No cells adhered to collagen types I and IV. Canine MCT cells from different origins expressed similar integrin patterns; however, there were some differences in adhesive behavior in response to various ECM proteins and activating stimuli.  相似文献   

11.
The ICR-derived glomerulonephritis (ICGN) mouse is an appropriate model for anemia associated with chronic renal disorder (CRD). Insufficient renal production of erythropoietin (EPO) induces the anemia associated with CRD. EPO mRNA is expressed in both kidneys and liver of progressing-stage ICGN mice. Hypoxic stimulation induced the EPO mRNA expression in the liver as well as in the kidneys of ICGN mice. The localization of EPO-producing cells in the liver remains controversial. Present study using an amplified in situ hybridization technique identified that nonparenchymal cells were the source of hepatic EPO production in ICGN mice under both normoxia and hypoxia.  相似文献   

12.
Extracellular matrix components (ECMs) in histological sections of the kidney cortex from the rats with adriamycin (ADR)-induced nephropathy (5 mg/kg, i.v.) were quantified by an immunohistochemical micromethod. Changes in kidney histopathology and urine and blood biochemistry were investigated. Enlarged kidneys were granular on the surface and pale in color in ADR-treated rats, and these rats had kidneys with glomeruli with expanded mesangial area and with capillary aneurysm. Severe albuminuria, hypoalbuminemia, hypercholesterolemia and disorders in other nephrotic parameters were observed in ADR-treated rats. Type I and IV collagens, fibronectin and laminin contents in the renal cortex of ADR-treated rats at 10 weeks were 329, 317, 263 and 295%, respectively, higher than in each vehicle control, and those at 28 weeks were 1,211, 930, 1,057 and 1,012%, respectively. The glomerular sclerotic abnormalities progressed in a time-dependent manner. Moreover, there was a strong correlation between the ECM levels and serum creatinine and blood urea nitrogen levels. In conclusion, microquantification provided useful information for accurate diagnosis and prognosis of nephrotic lesions and is a good tool to assess the advancement of renal disorders in patients with nephropathy.  相似文献   

13.
This study aimed to characterize the composition and distribution of the extracellular matrix (ECM) components in normal canine mitral valves (MV) and in chronic heart valve disease (CVD).MV of 50 dogs (normal (n = 9), mild (n = 13), moderate (n = 17), severe (n = 11) CVD) were investigated macroscopically, histologically (H.-E., picrosirius red) and immunohistochemically (collagen I, III, IV, V, VI, elastin, laminin, fibronectin, heparan sulphate).In normal MV, ECM components were expressed in a typical layered pattern. In mild CVD, basement membrane components (laminin, collagen IV, fibronectin) were increased. Advanced CVD was characterized by myxomatous nodular lesions displaying a marginal and a central region comprised mainly of collagen I, VI and fibronectin in the former and collagen I and III in the latter. Collagen IV and laminin appeared multifocally in marked CVD.In conclusion, not only an accumulation of proteoglycans, but also a distinctly altered expression of basement membrane components, and collagens characterizes CVD.  相似文献   

14.
Remodeling of uterine endometrial extracellular matrix (ECM) is pivotal to successful implantation and placentation, and has been well described in the rodents and humans. However, bovine endometrial ECM remodeling is still vaguely defined, especially at the time of implantation. Therefore, this study investigated the distribution of four ECMs namely, types I and IV collagen, laminin and fibronectin, from days 0 to 30 of gestation in bovine endometrium by immunofluorescence microscopy. A change in the distribution pattern of ECMs was evident by day 14 of gestation as features at this stage were clearly different from those of day 14 of the estrous cycle. The immunoreactivity of type I collagen, fibronectin and laminin decreased from day 14 of gestation and was obscured by day 24 of gestation. The type I collagen fibers formed were of thinner consistency than those of the estrous cycle and showed a coarser meshwork within the epithelium sites during the implantation period. In addition, the type IV collagen and laminin immunoreactivities of epithelial basement membrane also remarkably declined at exactly the same time. By day 30 of gestation, the four ECMs had regenerated with the formation of the placentome. In conclusion, this study reveals that remodeling of ECM is essential for the successful establishment of pregnancy in the bovine.  相似文献   

15.
ICGN is a partially inbred strain of mice with nephrotic syndrome caused by spontaneous glomerular lesion. It has been reported that the albuminuria in ICGN mouse was controlled by at least a single autosomal recessive gene (nep). In this study, we mapped the nep locus by linkage analysis of backcross progeny between ICGN and MSM mice using DNA pooling method. The linkage analysis revealed that the nep locus was localized on the distal part of chromosome 15.  相似文献   

16.
A pad equivalent for a dog was prepared as a substitute for the loss of footpad. In addition to the time course of formation on epidermal morphogenesis, we investigated expressions of alpha(6) integrin subunit as adhesive molecule, and laminin and type IV and VII collagens as extracellular matrices of basement membrane components. Epithelium of the pad equivalent was thick enough to be easily confirmed at 5 days at the air-liquid interface, but many creases appeared on it at 7 days, and it shrank at 10 and 14 days. Keratinocytes were increased in 4 to 5 cell layers at 1 day at the air-liquid interface, differentiating into basal cell layer. Granular and corneal cell layers were confirmed until 5 days, and maintained their shape at least until 14 days. Alpha 6 integrin was expressed at almost the same fluorescent intensity as native pad tissue at 1 day at the dermal-epidermal junction. Laminin and type IV collagen were intermittently expressed at 5 and 10 days, respectively, at the dermal-epidermal junction, and at 14 days the fluorescence showed almost the same intensity as native pad tissue. The expression of type VII collagen was discontinuous at 2 days at the dermal-epidermal junction, but remained as it was at 14 days. The present findings suggested that although the formation of anchoring fibrils in basement membrane was incomplete, the pad equivalent in the dog was reconstructed similar to a native pad by epidermal morphogenesis.  相似文献   

17.
The extracellular matrix (ECM) and specific ECM components can have a major influence on cell growth, development, and phenotype. The influence of the ECM and ECM components on adipogenesis in vivo and in vitro will be reviewed in this paper. Engelbreth-Holm-Swarm substratum and laminin per se markedly increased attachment, spreading, and hypertrophy of preadipocytes in serum-free primary cultures of porcine adipose tissue stromal-vascular cells. Furthermore, primary cultures of stromal-vascular cells showed that preadipocytes express ECM components after preadipocyte recruitment. Staining for plant lectins, type IV collagen, and laminin in fetal pig adipose tissue demonstrates that adipocyte reactivity for laminin was strong throughout fetal development and was similar for developing adipocytes and vasculature. However, lectin binding and type IV collagen reactivity of blood vessels preceded that for adipocytes. Therefore, these studies indicated that the ECM and in particular laminin may play a critical role in morphological aspects of preadipocyte development. Specific inhibitors and modulators of collagen synthesis have been used to evaluate the role of collagens in the differentiation of bovine intramuscular preadipocytes (BIP) and other preadipocyte cell lines. Triglyceride accretion of BIP cells was inhibited by a general inhibitor of collagen biosynthesis, whereas specific inhibitors or modulators of type IV collagen inhibited 3T3-L1 cell differentiation. Further study revealed that compared with collagens types I to IV, type V and VI collagens have an important and active role in BIP adipogenesis. The growth of intramuscular bovine adipose tissue may be dependent on collagen newly synthesized and organized by the adipocytes per se. The role of extracellular or ECM proteolysis in regulating adipogenesis also will be reviewed in this paper. Many members of the matrix metalloproteinase (MMP) family are expressed by adipocytes, and specific inhibition of MMP-9 greatly reduces adipogenesis in vitro. Possibly, MMP and other proteases regulate turnover of key adipocyte ECM proteins that are involved in the regulation of preadipocyte proliferation and differentiation.  相似文献   

18.
Renal specimens from 6 mink with encephalitozoonosis were studied by light and electron microscopy and immunohistochemistry. The glomeruli of affected kidneys had a mesangioproliferative glomerulonephritis which was characterized by an increase in mesangial cells and matrix in most glomeruli. Some glomeruli were partially or completely sclerosed. There were protein or granular casts in the cortical and medullary tubules. Interstitial nephritis, vasculitis and tubular cysts were found. Electron microscopy demonstrated extensive matrix and increased cellularity in the mesangial areas. Glomeruli showed segmentally thickened or wrinkled capillary basement membranes. Electron dense deposits were found in the glomerular basement membranes and mesangium. Peroxidase-anti-peroxidase immunohistochemistry demonstrated that IgG and IgM positive material was present as granular deposits in the glomerular basement membrane and occasionally in the mesangium.  相似文献   

19.
One of the approaches to preserve the properties of mesenchymal stem cells (MSCs) during in vitro expansion is to use cell culture substrates. MSCs are known to generate the extracellular matrix (ECM) proper to preserve their proliferative capacity in vitro, but extensive expansion is considered to deprive MSCs of the capacity to prepare such ECM. In order to examine the features of ECM proper that is required to preserve the proliferative capacity of MSCs, we analyzed the changes in the composition of ECM accumulated by MSCs during in vitro expansion. Biochemical and immunological analysis showed that collagen and laminin content decreased during expansion. Immunofluorescence and ultrastructural analyses showed that the ECM structure changed from a dynamic fibrous, porous and steric structure to a static, crammed, and planar one. The results of Western blotting analysis suggested loose intermolecular association in ECM molecules accumulated by extensively proliferated MSCs. The ECM prepared by extensively proliferated MSCs was less effective to recover their proliferative capacity than that prepared by less proliferated cells. Our results suggest that a cell culture substrate to expand MSCs requires abundance in collagen and basement membrane components, and steric, porous and fibrous structure in which ECM molecules are tightly associated.  相似文献   

20.
Laminin‐332 (laminin‐5) is a basement membrane heterotrimeric protein composed of alpha‐3, beta‐3 and gamma‐2 laminin chains. Laminin‐332 polypeptides are targeted by auto‐antibodies in human patients with mucous membrane (cicatricial) pemphigoid or, more rarely, subepidermal vesicular diseases that resemble epidermolysis bullosa acquisita (EBA) or bullous pemphigoid (BP). The objectives of this report were to characterize the clinical, histopathological and immunological characteristics of nine dogs with auto‐antibodies targeting laminin‐332. Immunological investigations consisted of direct immunofluorescence (IF), indirect IF with intact and salt‐split canine gingival, and salt‐split normal or laminin‐332‐deficient human skin, immunoblotting with purified human laminin‐332 and immunoblotting with recombinant NC1 domain of human collagen VII. All dogs exhibited varying degrees of skin blistering and ulceration associated with microscopic subepidermal vesiculation with or without inflammatory cells. Indirect IF established that circulating IgG auto‐antibodies bound the dermal side of salt‐split canine lip and human skin. In five dogs, IgG variably recognized the basement membrane of laminin‐332‐deficient human skin (three dogs negative, two dogs positive). In all nine dogs, IgG auto‐antibodies detected purified human laminin‐332 by immunoblotting. In two dogs, additional targeting of collagen VII‐NC1 was present. These observations establish laminin‐332 as a novel basement membrane antigen in dogs with autoimmune blistering diseases with variable clinical phenotypes. The names ‘acquired junctional epidermolysis bullosa’, ‘anti‐laminin‐332 mucous membrane pemphigoid (MMP)’ and ‘mixed auto‐immune subepidermal blistering dermatosis’ are proposed for dogs with clinical signs reminiscent of EBA, MMP or BP respectively.  相似文献   

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