Transforming growth factor-β1 mediated up-regulation of lysyl oxidase in the kidneys of hereditary nephrotic mouse with chronic renal fibrosis

Abstract

Lysyl oxidase (LOX), an extracellular enzyme, plays a key role in the post-translational modification of collagens and elastin, catalyzing inter- and intra-crosslinking reactions. Because the crosslinked extracellular matrices (ECMs) are highly resistant to degradative enzymes, it is considered that the over-expression of LOX may cause severe fibrotic degeneration. In the present study, we addressed the role of LOX-mediated crosslinking in chronic renal tubulointerstitial fibrosis using an animal model of hereditary nephrotic syndrome, the Institute of Cancer Research (ICR)-derived glomerulonephritis (ICGN) mouse. Ribonuclease protection assay (RPA) revealed that LOX mRNA expression was up-regulated in the kidneys of ICGN mice as compared with control ICR mice. High-level expression of LOX and transforming growth factor (TGF)-beta1 (an up-regulator of LOX) mRNA was detected in tubular epithelial cells of ICGN mouse kidneys by in situ hybridization. Type-I and -III collagens, major substrates for LOX, were accumulated in tubulointerstitium of ICGN mouse kidneys. The present findings imply that TGF-beta1 up-regulates the production of LOX in tubular epithelial cells of ICGN mouse kidneys, and the excessive LOX acts on interstitial collagens and catalyzes crosslinking reactions. As a result, the highly crosslinked collagens induce an irreversible progression of chronic renal tubulointerstitial fibrosis in the kidneys of ICGN mice.

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].…”

Localization of Tissue Transglutaminase (tTG) in Kidney of ICR-Derived Glomerulonephritis (ICGN) Mice

“…Excessive LOX interacts with interstitial collagens, catalyzing cross-linking reactions, resulting in highly cross-linked collagens. Thus LOX effects an irreversible progression of chronic renal tubulointerstitial fibrosis in the kidneys of ICGN mice [8].…”

“…In addition, extreme accumulation of collagens of interstitial types I and III was found in the severely affected cases [32]. A recent study indicated that transforming growth factor (TGF)-b1 increases the production of lysyloxidase (LOX) in the tubular epithelial cells of ICGN mouse kidneys [8]. Excessive LOX interacts with interstitial collagens, catalyzing cross-linking reactions, resulting in highly cross-linked collagens.…”