ABSTRACT. 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 ki dneys 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-α 1 (I), -α 1 (III) and -α 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 in jured 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, ext reme 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. KEY WORDS: extracellular matrix (ECM), ICR-derived glomerulonephritis (ICGN) mouse, in situ hybridization, type I, III and IV collagen mRNA.J. Vet. Med. Sci. 66(2): 123-128, 2004 Institute of Cancer Research (ICR)-derived glomerulonephritis (ICGN) mice, a novel inbred strain of mice with a hereditary nephrotic syndrome of unknown etiology, were established in the National Institute of Infectious Diseases (NIID, Tokyo, Japan) and considered a good model of human idiopathic nephrotic syndrome [14][15][16][17][18][19][20]. The ICGN mice develop proteinuria, hypoproteinemia and hyperlipidemia, and approximately 40% of aged (more than 30-week-old) mice develop severe systemic edema. Conventional histopathological analyses demonstrated glomerular lesions consisting of thickened basement membranes of the capillary loops with irregular sprike-like protrusions and enlargement of the mesangial area accompanied by cellular proliferation [14,15,19,20]. Ultrastructurally, multilaminar splitting of the lamina densa of the thickened glomerular basement membrane and fusion of the epithelial foot process were noted [14,15]. The characteristic changes in the structure of cell-surface carbohydrates histochemically estimated with 24 different lectins were seen in the tubulointerstitial cells in ICGN m ice [25]. Previou sly , w e immunohistochemically showed that excessive accumulation of type I, III and IV collagens was demonstrated in glomeruli and tubulointerstitum of ICGN mice as compared with those ...
ABSTRACT. 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. The ICR-derived glomerulonephritis (ICGN) mouse established in the National Institute of Infectious Diseases (NIID; Tokyo, Japan) is a novel inbred mouse strain with a hereditary nephrotic syndrome of unknown etiology, and considered to be a good model of human idiopathic nephrotic syndrome [13][14][15][16]. Homozygous ICGN mice show proteinuria at a young age, later develop hypoproteinemia, hyperlipidemia, severe anemia and systemic edema, and eventually die as a result of chronic renal disorder (CRD) [15]. Our previous studies [20][21][22][23]25] showed that most of the renal tubules expanded and many kinds of extracellular matrix (ECM) components, both interstitial and basement membrane components, abnormally accumulated in glomeruli and tubulointerstitium of ICGN mouse kidneys. The progress of fibrotic degeneration in ICGN mouse kidneys may be caused by overproduction of ECM components, inhibition of ECM breakdown, and decreased activities of matrix metalloproteinases [22]. Apoptotic cells or proliferating cells were detected only in the kidneys of ICGN mice but not those of normal ICR mice [25]. In the kidneys of ICGN mice, apoptotic cells with large round nuclei were observed only in the tubulointerstitium, and proliferating cells were detected in epithelial cells of distal renal tubules. Age-dependent increases in apoptotic cell and proliferating cell densities were also noted. Such irregular cellular kinetics may cause renal dysfunction in ICGN mice.Anemia with CRD (renal anemia) is a major subsequent symptom in patients with CRD. The hematocrit levels are less than 30% in CRD patients and the condition of renal anemia directly affects their quality of life [8,18]. The lack of appropriate animal models for CRD means that the precise cause of renal anemia is unknown, however, it has been established that the lack of ...
The Institute of Cancer Research (ICR)-derived glomerulonephritis (ICGN) mouse is a hereditary model animal for nephrotic syndrome with chronic renal tubulointerstitial fibrosis. In most fibrotic diseases, myofibroblastic differentiation is considered to play crucial roles in pathogenesis of fibrosis and is dominantly regulated by the transforming growth factor (TGF)-beta1 signaling system. To reveal the pathogenic mechanism of chronic renal fibrosis in ICGN mice, we examined the expression and localization of TGF-beta1 signal transducer proteins (TGF-beta receptor-I and -II, Smad2/3 and Smad4) in kidney sections and in primarily cultured tubulointerstitial fibroblasts (TIFs). In kidneys of ICGN mice, many tubulointerstitial cells were differentiated to myofibroblastic cells and were alpha-smooth muscle actin (alphaSMA)-positive. The numbers of alphaSMA-positive TIFs prepared from kidneys of ICGN mice (ICGN-TIFs), but not those of ICR control mice (ICR-TIFs), increased during cell culture. No significant differences in production or activation of TGF-beta1 between ICGN-TIFs and ICR-TIFs were seen by enzyme-linked immunosorbent assay. In vitro transcriptional reporter assay for TGF-beta1 and Western immunoblotting for TGF-beta1 signal transducers showed no notable differences in the expression levels of TGF-beta receptor-I or -II or Smad2/3 between these TIFs. However, augmented cytoplasmic Smad4 protein in ICGN-TIFs, but not ICR-TIFs, seemed to cause hypersensitivity against TGF-beta1, and the eventual nuclear localization of Smad2/3-Smad4 complex was increased in ICGN-TIFs. Thus, the abnormal cytoplasmic augmentation of Smad4 induces acceleration of TGF-beta1 signaling in the renal tubulointerstitial cells of ICGN mice.
It has been proposed that serotonin (5-HT) facilitates the chemosensory activity of the carotid body (CB). In the present study, we investigated mRNA expression and immunohistochemical localization of the 5-HT synthetic enzyme isoforms, tryptophan hydroxylase 1 (TPH1) and TPH2, and the 5-HT plasma membrane transport protein, 5-HT transporter (SERT), in the CB of the rat. RT-PCR analysis detected the expression of mRNA for TPH1 and SERT in extracts of the CB. Using immunohistochemistry, 5-HT immunoreactivity was observed in a few glomus cells. TPH1 and SERT immunoreactivities were observed in almost all glomus cells. SERT immunoreactivity was seen on nerve fibers with TPH1 immunoreactivity. SERT immunoreactivity was also observed in varicose nerve fibers immunoreactive for dopamine beta-hydroxylase, but not in nerve fibers immunoreactive for vesicular acetylcholine transporters or nerve terminals immunoreactive for P2X3 purinoreceptors. These results suggest that 5-HT is synthesized and released from glomus cells and sympathetic nerve fibers in the CB of the rat, and that the chemosensory activity of the CB is regulated by 5-HT from glomus cells and sympathetic nerve fibers.
S U M M A R Y Neurochemical and morphological changes in the carotid body are induced by chronic hypoxia, leading to regulation of ventilation. In this study, we examined the time courses of changes in immunohistochemical intensity for tyrosine hydroxylase (TH) and cellular volume of glomus cells in rats exposed to hypoxia (10% O 2 ) for up to 24 hr. Grayscale intensity for TH immunofluorescence was significantly increased in rats exposed to hypoxia for 12, 18, and 24 hr compared with control rats (p,0.05). The transectional area of glomus cells was not significantly different between experimental groups. The TH fluorescence intensity of the glomus cells exhibited a strong negative correlation with the transectional area in control rats (Spearman's ρ 5 20.70). This correlation coefficient decreased with exposure time, and it was lowest for the rats exposed to hypoxia for 18 hr (ρ 5 20.18). The histogram of TH fluorescence intensity showed a single peak in control rats. The peaks were gradually shifted to the right and became less pronounced in hypoxia-exposed rats, suggesting that a hypoxiainduced increase in TH immunoreactivity occurred uniformly in glomus cells. In conclusion, this study demonstrates that short-term hypoxia induces an increase in TH protein expression in rat carotid body glomus cells. (J Histochem Cytochem 58:839-846, 2010)
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