Alpha macroglobulins and the low-density-lipoprotein-related protein/alpha-2-macroglobulin receptor in experimental renal fibrosis

Harry Van Goor, Jonathan R. Diamond, Guohua Ding, George Kaysen

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)35-43
Number of pages9
JournalExperimental Nephrology
Volume7
Issue number1
StatePublished - Jan 1999

Fingerprint

LDL-Receptor Related Proteins
Low Density Lipoprotein Receptor-Related Protein-1
alpha-Macroglobulins
Fibrosis
Peptide Hydrolases
Kidney
Macroglobulins
Glomerular Mesangium
Staining and Labeling
Metalloproteases
Serine Proteases
Dendritic Cells
Extracellular Matrix
Fibroblasts
Western Blotting
Immunohistochemistry
Macrophages

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 journalArticle

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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.",
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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.

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