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1.
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   

2.
Fibrotic degeneration was examined in the kidneys of ICR-derived glomerulonephritis (ICGN) mice, a novel inbred mouse line with a hereditary nephrotic syndrome of unknown etiology considered to be a good model of human idiopathic nephrotic syndrome. In the present study, we histochemically revealed changes in accumulation of extracellular matrix (ECM) components and in localization of integrins, cellular receptors for ECM, in the kidneys of ICGN mice with the progression of renal failure. Excessive accumulation of basement membrane (laminin and collagen IV) and interstitial (type III collagen) ECM components were demonstrated in the glomeruli and tubulointerstitum of ICGN mice. Marked deposition of type I collagen and tenascin was seen only in the glomeruli of ICGN mice but not in those of ICR mice as normal controls. Increased expression of integrin alpha1-, alpha2-, alpha5- and beta1-subunits in glomeruli with fibrotic degeneration and abnormal distribution of alpha6-subunit were noted in the kidneys of ICGN mice. Excessive laminin, a ligand of alpha6beta1-integrin, was demonstrated on the tubular basement membrane, but alpha6-subunit diffusely disappeared on the basal side of the tubular epithelial cells. We presumed that abnormal integrin expression in renal tubules causes epithelial cell detachment, and consequently tubular nephropathy, and results in disorder of ECM metabolism causing excessive accumulation of ECM components in the kidneys of ICGN mice.  相似文献   

3.
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   

4.
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   

5.
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   

6.
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   

7.
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   

8.
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   

9.
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   

10.
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   

11.
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   

12.
Diffuse mesangial sclerosis (DMS) is one of the hereditary glomerular diseases and histologically characterized by severe glomerulosclerosis and subsequent tubulo-interstitial fibrosis (TIF). In DMS patients, renal dysfunction correlates well with TIF, rather than with glomerular lesions. Thus, molecular mechanisms whereby TIF in DMS progresses should be addressed. Previously, we found that nephrotic ICGN mice manifest DMS-like lesions and develop renal dysfunction in accordance with onset of TIF. In the present study, we investigated fibrogenic events involved in the progression of TIF after DMS manifestation, using the DMS mouse model. Immunohistochemistry revealed that expression of transforming growth factor-beta (TGF-beta) was rare in the interstitial cells of the nephrotic mice at the early-stage of DMS, while the TGF-beta expression became evident in the late-stage DMS mice. Platelet-derived growth factor (PDGF) was mildly expressed in the distal tubules of the early-stage DMS mice, whereas the PDGF expression markedly increased at the late-stage of DMS. As a result, alpha-actin-positive myofibroblastic cells were found dominant in the interstitial spaces of the late-stage DMS mice. Finally, TIF became severe in accordance with the overexpressions of these molecules. Our results suggest that in our murine model: 1) persistent proteinuria leads to over-expression of TGF-beta and PDGF in non-glomerular areas; 2) these cytokines provoke interstitial myofibroblast accumulation; and 3) the myofibroblasts produce fibrotic matrix proteins in the interstitial spaces. This process may possibly contribute to the development of TIF in DMS patients.  相似文献   

13.
In the present study, we investigated the sexual dimorphisms, effects of castration and sex hormone treatment, and strain differences in the morphology of mouse kidney by measuring the percentage of renal corpuscles with cuboidal cells in the parietal layer of the glomerular capsule, the diameter of renal corpuscles and the number of nuclei of epithelial cells in the proximal convoluted tubule. In ICR mice, the percentage of renal corpuscles with cuboidal cells and the diameter of renal corpuscles were larger in males than in females, and the numbers of nuclei were lower in males than in females. All of these parameters became similar to those of intact females by orchiectomy, and restored to levels similar to those in intact males after testosterone treatment to orchiectomized males. On the other hand, ovariectomy and estradiol treatment gave no effects to any of these parameters. Similar sexual dimorphisms were observed in BALB/c, C57BL/6, C3H/He and DBA/2 mice as in ICR mice, although the diameter of renal corpuscles was not significantly different between males and females in BALB/c mice. Strain differences were observed in each of these three parameters among the 5 strains. In conclusion, the present study demonstrated sexual dimorphisms, effects of castration and sex hormone treatment, and strain differences in the morphology of mouse kidney by morphometrical analysis.  相似文献   

14.
Glomerular lesions including membranoproliferative glomerulonephritis occur spontaneously in aged mice, but they are rare in young animals. In our laboratory, spontaneous glomerulonephritis was observed in an 8-week-old male Crj:CD1 (ICR) mouse. Macroscopically, the bilateral kidneys were discolored, but no edema or ascites was observed. Glomerular lesions were characterized by a thickening of capillary walls, a double-contoured basement membrane and mesangial expansion due to increased amounts of matrix. Ultrastructurally, mesangial interposition in the capillary wall and subendothelial deposition of basement membrane-like material were observed. No evidence of immune complex deposition or amyloid was found. On the basis of the observed clinical pathology and histopathology, a secondary form of glomerular lesion was excluded. The glomerular lesion was compatible with glomerulonephritis in a young Crj:CD1 (ICR) mouse.  相似文献   

15.
Ghrelin is a peptide hormone that is mainly produced by the stomach. The kidney is a major source of local ghrelin, and maintaining body fluid balance is considered a critical role of renal ghrelin. However, there are no reports on renal ghrelin in small animal medicine. The present study investigated the intrarenal localization of and change in ghrelin expression in dogs with immune complex-mediated glomerulonephritis (ICGN). Ghrelin immunoreactivity (IR) was observed in the distal tubules of normal kidneys. Ghrelin IR was weak in ICGN kidneys, and the quantitative ghrelin IR score was significantly lower in ICGN kidneys than in normal kidneys. In cases of ICGN, plasma creatinine concentrations showed a positive correlation with the ghrelin IR score.  相似文献   

16.
This report describes spontaneous cytoplasmic vacuolation in the proximal renal tubules of a 7-week-old male ICR [Crlj:CD1(ICR)] mouse. The contents of vacuoles were positively stained with periodic acid-Schiff (PAS) and Sudan black, and the membranes were positive on immunohistochemical staining for lysosomal-associated membrane protein-2 (LAMP-2), a marker of lysosomal membrane. Electron microscopy revealed electron-dense lamellar bodies in the proximal tubular epithelial cells. These histopathological features are similar to those in α-galactosidase A-deficient mice, in which globotriaosylceramide (Gb3), a glycosphingolipid, accumulates in lysosomes. When we performed immunohistochemical staining for Gb3, the contents of vacuoles were positively stained. From these results, spontaneous cytoplasmic vacuolation in the proximal renal tubules in the mouse was identified as lysosomal accumulation of Gb3.  相似文献   

17.
The kidneys of non-diabetic NOD and wild type ICR mice were examined morphometrically at 3 and 6 months of age. Kidney weights and diameter of renal corpuscles of non-diabetic NOD mice were less than those of ICR mice. No lesions were observed in glomeruli or uriniferous tubules. Renin-positive areas were more common in NOD mice than in ICR mice, but no differences were detected in the Western blot analyses.  相似文献   

18.
The nonobese diabetic mouse is a model of spontaneous insulin-dependent diabetes mellitus. The present study made longitudinal observations of renal lesions in the acute-progressive phase of diabetic mice 0, 10, 20, 30, and 40 days after onset of diabetes without insulin therapy. Plasma creatinine and blood urea nitrogen concentrations gradually increased after onset of diabetes. Kidney weight increased and plateaued at day 20. Under electron microscopy the glomeruli demonstrated only mild changes on day 40. In the proximal tubules proliferating cell nuclear antigen-positive nuclei and nuclear divisions were increased on days 10 and 20. On day 40 of diabetes, increased periodic acid-Schiff-positive granules, confirmed as lysosomal dense bodies, increased neuronal nitric oxide synthase (nNOS) positive reaction, and decreased periodic acid-Schiff staining in the brush border were observed in the proximal straight tubules. In the juxtaglomerular apparatus stratified macula densa were decreased with time in diabetes compared with the findings on day 0, and this macula densa positively reacted with nNOS. No changes in renin levels were observed. In addition, apoptotic cells were not detected. In conclusion, this research represents the first thorough characterization of acute changes in nonobese diabetic mouse kidneys. The results demonstrated renal hypertrophy and slight glomerular injury in early stages and structural alteration of the proximal straight tubules at later stages during the acute phase of diabetes. Furthermore, increased nNOS may represent one of the pathogenic factors of diabetic nephropathy.  相似文献   

19.
Hepatoblastomas from B6C3F1 and BALB/c mice were examined by light and electron microscopy and by immunohistochemical reactions for alpha-fetoprotein, keratin, and vimentin. Tumors occurred in one group of a chronic bioassay for the interaction of diet, genetic strain, and the carcinogen, 2-acetylaminofluorene. Tumors had several populations (including epithelial and mesenchymal cells) in various stages of differentiation. Neoplastic epithelial cells had features of embryonal hepatocytes, such as sparse cytoplasmic organelles, absence of glycogen, abundant free ribosomes, occasional bile canaliculi, and peroxisome-like dense bodies. Embryonal fibroblast-like cells had pleomorphic and folded nuclei with prominent perinuclear chromatin and dispersed cytoplasmic organelles. Fibroblast-like cells were surrounded by bundles of collagen fibrils. Intermediate or transitional types of cells were seen. No tumor cells were immunoreactive for mouse alpha-fetoprotein (AFP) antibody, unlike those in hepatocellular adenomas or carcinomas. Epithelial and mesenchymal tumor cells contained intermediate filaments throughout the cytoplasm; some of these cells stained for keratin but not for vimentin. These findings suggest that mouse hepatoblastomas are derived from bipotential liver blastema cells and are composed of a mixture of several cell populations.  相似文献   

20.
This investigation was initiated to study and correlate the clinical and ultrastructural aspects of glomerulonephritis induced in the laboratory mouse by the intraperitoneal injection of a sublethal dose of murine cytomegalovirus. An attempt was made to ascertain the pathogenesis of the glomerular changes and the resultant viremia. Murine cytomegalovirus infection caused an acute transient glomerulonephritis in young female mice of the HA/ICR strain. Mice that survived a sublethal inoculation of homogenized infected gland developed transient proteinuria and excreted tubular casts. The murine cytomegalovirus infection resulted in a glomerular lesion that was selective for the mesangial cell. After entering the mesangial cell by phagocytosis the virus replicated in the nucleus and was excreted into the channel of the mesangial matrix, with extension toward the periphery of the capillary loop and adjacent to the urinary space. Virus particles were rarely found in the glomerulus after the 5th day of infection and chronic renal disease was not observed.  相似文献   

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