Abstract
In this study, we evaluated the location of non-specific proteinase inhibitors and their receptor in experimental glomerular and interstitial fibrosis. The alpha macroglobulins alpha-2-macroglobulin (α2M) and alpha-1- inhibitor 3 (α113) are proteinase inhibitors, including metalloproteinases and serine proteases. Using immunohistochemistry, we detected α113 in the glomerular mesangium in control rats. In acute and chronic fibrosis, the α113 protein expression was dramatically increased throughout the glomerulus and at sites of increased extracellular matrix deposition in the interstitium. The presence of α113 in normal and nephrotic kidneys was confirmed by Western blotting. Under chemically reducing conditions, we found that, in contrast to native α1/3, kidney-derived α1/3 has reacted upon by proteinases, thereby revealing a functional role for this macroglobulin under normal and pathological conditions. Double staining revealed that high amounts of glomerular α1/3 were present in sclerotic lesions. α2M was absent in glomeruli and interstitium from control rats, but present in small amounts in glomerular mesangial areas of acute nephrotic rats. α2M was also present in significant amounts in glomeruli from rats with chronic fibrosis. The receptor mediating the uptake of proteinase inhibitor-proteinase complexes, the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor, was found in the glomerular mesangium and tubulo-interstitium from control rats. Significant increments in receptor expression were found in glomeruli and interstitium of rats with chronic fibrosis, with a preferential localization in fibrotic areas. Interstitial staining for low-density- lipoprotein-related protein/alpha-2-macroglobulin receptor was attributed to fibroblasts, since double staining ruled out dendritic cells and macrophages. In conclusion, these studies demonstrate the intrarenal presence of plasma- derived proteinase inhibitors together with their receptors. These findings may point to a novel mechanism for renal fibrosis wherein matrix-degrading proteinases are inhibited, resulting in renal fibrosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 35-43 |
| Number of pages | 9 |
| Journal | Experimental Nephrology |
| Volume | 7 |
| Issue number | 1 |
| State | Published - Jan 1999 |
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Keywords
- Alpha-1-inhibitor 3
- Alpha-2-macroglobulin
- Fibrosis
- Kidney
- Low-density- lipoprotein-related protein
- Proteinase inhibition
ASJC Scopus subject areas
- Nephrology
Cite this
Alpha macroglobulins and the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor in experimental renal fibrosis. / Van Goor, Harry; Diamond, Jonathan R.; Ding, Guohua; Kaysen, George.
In: Experimental Nephrology, Vol. 7, No. 1, 01.1999, p. 35-43.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alpha macroglobulins and the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor in experimental renal fibrosis
AU - Van Goor, Harry
AU - Diamond, Jonathan R.
AU - Ding, Guohua
AU - Kaysen, George
PY - 1999/1
Y1 - 1999/1
N2 - In this study, we evaluated the location of non-specific proteinase inhibitors and their receptor in experimental glomerular and interstitial fibrosis. The alpha macroglobulins alpha-2-macroglobulin (α2M) and alpha-1- inhibitor 3 (α113) are proteinase inhibitors, including metalloproteinases and serine proteases. Using immunohistochemistry, we detected α113 in the glomerular mesangium in control rats. In acute and chronic fibrosis, the α113 protein expression was dramatically increased throughout the glomerulus and at sites of increased extracellular matrix deposition in the interstitium. The presence of α113 in normal and nephrotic kidneys was confirmed by Western blotting. Under chemically reducing conditions, we found that, in contrast to native α1/3, kidney-derived α1/3 has reacted upon by proteinases, thereby revealing a functional role for this macroglobulin under normal and pathological conditions. Double staining revealed that high amounts of glomerular α1/3 were present in sclerotic lesions. α2M was absent in glomeruli and interstitium from control rats, but present in small amounts in glomerular mesangial areas of acute nephrotic rats. α2M was also present in significant amounts in glomeruli from rats with chronic fibrosis. The receptor mediating the uptake of proteinase inhibitor-proteinase complexes, the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor, was found in the glomerular mesangium and tubulo-interstitium from control rats. Significant increments in receptor expression were found in glomeruli and interstitium of rats with chronic fibrosis, with a preferential localization in fibrotic areas. Interstitial staining for low-density- lipoprotein-related protein/alpha-2-macroglobulin receptor was attributed to fibroblasts, since double staining ruled out dendritic cells and macrophages. In conclusion, these studies demonstrate the intrarenal presence of plasma- derived proteinase inhibitors together with their receptors. These findings may point to a novel mechanism for renal fibrosis wherein matrix-degrading proteinases are inhibited, resulting in renal fibrosis.
AB - In this study, we evaluated the location of non-specific proteinase inhibitors and their receptor in experimental glomerular and interstitial fibrosis. The alpha macroglobulins alpha-2-macroglobulin (α2M) and alpha-1- inhibitor 3 (α113) are proteinase inhibitors, including metalloproteinases and serine proteases. Using immunohistochemistry, we detected α113 in the glomerular mesangium in control rats. In acute and chronic fibrosis, the α113 protein expression was dramatically increased throughout the glomerulus and at sites of increased extracellular matrix deposition in the interstitium. The presence of α113 in normal and nephrotic kidneys was confirmed by Western blotting. Under chemically reducing conditions, we found that, in contrast to native α1/3, kidney-derived α1/3 has reacted upon by proteinases, thereby revealing a functional role for this macroglobulin under normal and pathological conditions. Double staining revealed that high amounts of glomerular α1/3 were present in sclerotic lesions. α2M was absent in glomeruli and interstitium from control rats, but present in small amounts in glomerular mesangial areas of acute nephrotic rats. α2M was also present in significant amounts in glomeruli from rats with chronic fibrosis. The receptor mediating the uptake of proteinase inhibitor-proteinase complexes, the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor, was found in the glomerular mesangium and tubulo-interstitium from control rats. Significant increments in receptor expression were found in glomeruli and interstitium of rats with chronic fibrosis, with a preferential localization in fibrotic areas. Interstitial staining for low-density- lipoprotein-related protein/alpha-2-macroglobulin receptor was attributed to fibroblasts, since double staining ruled out dendritic cells and macrophages. In conclusion, these studies demonstrate the intrarenal presence of plasma- derived proteinase inhibitors together with their receptors. These findings may point to a novel mechanism for renal fibrosis wherein matrix-degrading proteinases are inhibited, resulting in renal fibrosis.
KW - Alpha-1-inhibitor 3
KW - Alpha-2-macroglobulin
KW - Fibrosis
KW - Kidney
KW - Low-density- lipoprotein-related protein
KW - Proteinase inhibition
UR - http://www.scopus.com/inward/record.url?scp=0032903697&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032903697&partnerID=8YFLogxK
M3 - Article
C2 - 9892812
AN - SCOPUS:0032903697
VL - 7
SP - 35
EP - 43
JO - Experimental Nephrology
JF - Experimental Nephrology
SN - 0028-2766
IS - 1
ER -