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Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis
Jan-Stephan F Sanders1, Harry van Goor, Roeland Hanemaaijer
1Department of Internal Medicine, Division of Clinical Immunology, University Hospital Groningen, The Netherlands. j.sanders@int.azg.nl
Background:
Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
Methods:
Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages.
Results:
MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy.
Conclusions:
Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.
Insights
Matrix metalloproteinases (MMPs) and TIMP-1 are elevated in active ANCA-associated glomerulonephritis, correlating with kidney inflammation. This study highlights their role in active kidney disease, offering potential biomarkers for disease activity.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Matrix metalloproteinases (MMPs) and their inhibitors (TIMP-1) are implicated in renal inflammatory conditions.
- Their expression may correlate with the activity of glomerulonephritis.
Purpose of the Study:
- To analyze renal expression of MMPs, TIMP-1, and inflammatory cell markers in active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
- To correlate these expressions with disease activity and renal function.
Main Methods:
- Immunohistochemistry was used to assess MMP-2, -3, -9, TIMP-1, cathepsin G, neutrophil elastase, myeloperoxidase (MPO), and CD14 in renal biopsies.
- Double labeling identified MMPs and TIMP-1 in neutrophils (MPO) and macrophages (CD68).
Main Results:
- MMP-2, -3, -9, and TIMP-1 were significantly increased in glomeruli and tubulo-interstitium of active ANCA-associated glomerulonephritis patients, predominantly in inflammatory cells.
- Glomerular MMPs and TIMP-1 correlated with inflammatory markers (cathepsin G) and crescent formation.
- Tubulo-interstitial MMP expression correlated with neutrophil/monocyte infiltration and renal function.
Conclusions:
- Glomerular and interstitial expression of MMP-2, -3, -9, and TIMP-1 is elevated in active ANCA-associated glomerulonephritis.
- These MMPs and TIMP-1 correlate with key indicators of inflammatory activity in the kidney.
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