Decreased Matrix Metalloproteinase Activity in the Kidneys of Hereditary Nephrotic Mice (ICGN Strain)

Abstract

Abnormalities of extracellular matrix (ECM) metabolism, i.e., overproduction and/or inhibition of ECM breakdown, may contribute to progression of fibrotic degeneration in the kidney. Earlier studies revealed that major ECM components, type I, III, and IV collagens, etc., were accumulated in glomeruli and tubulointerstitium in kidneys of Institute of Cancer Research (ICR) derived glomerulonephritis (ICGN) mice which are a novel inbred strain of mice with a hereditary nephrotic syndrome of unknown etiology and are considered to be a good model of human idiopathic nephrotic syndrome. In the present study, we compared the activities of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components, in the kidneys of aged ICGN mice and age-matched ICR mice as normal controls. We biochemically measured interstitial collagenase (MMP-1), gelatinase (MMP-2 and MMP-9), and stromelysin (MMP-3) activities in the kidney tissues. Lower activities of MMP-1 and MMP-2 and MMP-9 were demonstrated in the kidneys of ICGN mice as compared with those of ICR mice, but there were no significant differences in the MMP-3 activities between these strains. These results show that decreased MMP activities cause abnormal accumulation of ECM in ICGN mouse kidneys.

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.…”

“…Notably, GBM components are accumulated at the earliest stage of renal fibrosis in the kidneys of ICGN mice [14]. Previously, we demonstrated that low levels of MMPs that degrade ECM components resulted in the renal fibrosis in these mice [20,23]. 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.…”

“…Previously, we demonstrated that low levels of MMPs that degrade ECM components resulted in the renal fibrosis in these mice [20,23]. 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].…”

“…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]. However, the expression of MMP-2 and MMP-9 was observed at renal tubules but not glomeruli [23].…”

“…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].…”