Abnormalities of Extracellular Matrices and Transforming Growth Factor .BETA.1 Localization in the Kidney of the Hereditary Nephrotic Mice (ICGN Strain).

Abstract

ABSTRACT. 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 β1 (TGF-β1). 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-β1 was also detected only in glomeruli of ICGN mice, but not in those of ICR mice. Furthermore, strikingly increased α-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-β1 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.-KEY WORDS: extracellular matrix, hereditary nephrotic syndrome, ICGN mouse, immunohistochemistry, transforming growth factor-β1.J. Vet. Med. Sci. 61 (7): [769][770][771][772][773][774][775][776] 1999 idiopathic nephrotic syndrome. The extracellular matrix (ECM) components play important roles in maintenance of the homeostasis of kidney functions [1,13,24]. The relationship between ECM and cells that adhere to it can play important regulatory roles in many basic cellular processes by influencing enzyme activity and phospholipid metabolism and by modifying transcriptional and translational activities of the cell. These regulatory influences can control key events in the life of a cell such as cell motility, proliferation, growth, differentiation and death. Disruption of existing cellular interactions with the ECM, due to experimental, pathological, or normal physiological changes, were also shown in early studies to be closely linked to changes in the functional capacity of cells. Early investigations showed that cell-substratum contact is closely linked to cell growth and cell death, that the relationship between substratum contact and cell growth and differentiation is positive for nonpathological cells, and that abnormalities in ECM-cell interaction plays a key role in the cause of diseases. In the kidney, the structure of the ECM is complex in terms of the multiplicity of different molecules, their spatial organization, and their anatomical distribution. Ty...

Dysfunction of Erythropoietin-Producing Interstitial Cells in the Kidneys of ICR-derived Glomerulonephritis (ICGN) Mice

“…As previously reported [9,29,[31][32][33][34][35][36], sclerotic glomeruli, highly expanded or occluded renal tubules, and appearance of cysts were observed in the kidneys of the progressing stage of ICGN mice compared to ICR control mice. The brush border of the expanded proximal tubules showed weakened intensity of PAS staining, whereas the glomeruli showed stronger intensity ( Fig.…”

“…Homozygous ICGN mice exhibit proteinuria at a young age, later develop hypoproteinemia, hyperlipidemia, severe anemia and systemic edema, and eventually die as a result of CRD [20,21]. In the kidneys, most of the renal tubules expand and many kinds of extracellular matrix (ECM) components accumulate abnormally in glomeruli and the tubulointerstitium because of the overproduction and stabilization of ECM components, and the inhibition of ECM breakdown [9,29,[31][32][33]. Irregular cellular kinetics are also noted in ICGN mice, and age-dependent increases in apoptotic cell and proliferating cell densities have been reported [34].…”

Expression of Macrophage Metalloelastase (MMP-12) in Podocytes of Hereditary Nephrotic Mice (ICGN Strain)

“…Our previous studies [2,3,[19][20][21][22][23] and the present findings indicate that the ICGN mouse is a unique model for studying the mechanisms of glomerular injury and renal fibrosis. This is the first report that an enzyme that degrades the ECM contributes to glomerular injury in ICGN mice.…”

“…The ICGN strain, an experimental model for human idiopathic nephrotic syndrome, shows an excessive accumulat i o n o f E C M c o m p o n e n t s i n g l o m e r u l a r a n d tubulointerstitial regions [2,3,19,21,22]. Notably, GBM components are accumulated at the earliest stage of renal fibrosis in the kidneys of ICGN mice [14].…”

“…Histological studies show a thickened glomerular basement membrane (GBM) and effacement of podocyte foot processes at an early age [9][10][11][12][13][14]. We previously found that components of the extracellular matrix (ECM) accumulate in the glomeruli and tubulointerstitium of ICGN kidneys [2,3,19], and that the accumulation was due to hyper-production and less degradation of the ECM components [20,21,23]. We measured biochemically the activity and the expression level of matrix metalloproteinase (MMP)-2 and MMP-9 in ICGN kidneys, and found decreased levels in comparison with normal ICR mice [20].…”