Changes in the Localization of Type I, III and IV Collagen mRNAs in the Kidneys of Hereditary Nephritic (ICGN) Mice with Renal Fibrosis

Abstract

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 ...

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.…”

“…We found decreased levels of gelatinases (MMP-2, -9), which degrade basement membrane (BM) components such as type IV collagen, and membrane type1 MMP, in the kidneys [20,23], but their expression mainly occurred in renal tubules. The accumulation of BM components was observed in glomeruli, but the production of BM compo- nents was not markedly increased [21]. The precise mechanism for the accumulation of BM components in the glomeruli of ICGN mice remains unclear.…”

“…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].…”

Decreased Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinase in the Kidneys of Hereditary Nephrotic (ICGN) Mice

“…Early stage (8-week-old; slightly renal fibrosis) and terminal stage (15-week-old: progressed stage of renal fibrosis) male homozygous ICGN mice from a specific-pathogen-free colony in NIID [16][17][18] and age-and sex-matched ICR mice pur-…”