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The role of ADAM 15 in glomerular mesangial cell migration
John Martin1, Lisa V Eynstone, Malcolm Davies
1Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, Wales, UK. martinj1@cf.ac.uk
Abstract:
Mesangial cells (MC) occupy the core of the renal glomerulus and are surrounded by a mesangial matrix. In certain diseases, MC migrate through this matrix into the pericapillary space. The mechanisms involved, however, are poorly understood. Members of the ADAM (A Disintegrin And Metalloproteinase) family of membrane proteins have the potential to be key modulators of cell-matrix interactions through the activities of their constituent domains. We have studied the possible role of ADAM 15 in human (H) MC migration in vitro. HMC ADAM 15 was expressed at low levels in serum-free medium but was increased during migration. Antibodies to the individual domains of ADAM 15 and the incorporation of antisense ADAM 15, (but not control oligonucleotide) inhibited this migration. Furthermore, inhibition of migration by the broad spectrum metalloproteinase inhibitor BB3103, demonstrated that metalloproteinase activity was essential for migration. ADAM 15, extracted from HMC membranes, was an active metalloproteinase, which degraded both type IV collagen and gelatin prepared from fibrillar collagen. Activity was inhibited by EDTA but not by phenylmethylsulfonyl fluoride. This is the first report of the potential of ADAM 15 for involvement in the restructuring of the mesangial matrix and in the migration of MC in disease.
Insights
ADAM 15 (A Disintegrin And Metalloproteinase 15) facilitates human mesangial cell (MC) migration by degrading extracellular matrix. This finding suggests ADAM 15
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Mesangial cells (MC) are crucial components of the renal glomerulus.
- MC migration into the pericapillary space occurs in certain kidney diseases.
- The mechanisms driving MC migration are not well understood.
Purpose of the Study:
- To investigate the role of ADAM 15 (A Disintegrin And Metalloproteinase 15) in human MC migration.
- To explore the potential of ADAM 15 as a modulator of cell-matrix interactions in the kidney.
Main Methods:
- Studied human MC migration in vitro.
- Utilized antibodies against ADAM 15 domains and antisense oligonucleotides.
- Assessed the effect of metalloproteinase inhibitors and characterized ADAM 15 enzymatic activity.
Main Results:
- ADAM 15 expression increased during MC migration.
- Inhibition of ADAM 15 or its metalloproteinase activity significantly reduced MC migration.
- Extracted ADAM 15 demonstrated metalloproteinase activity, degrading type IV collagen and gelatin.
Conclusions:
- ADAM 15 plays a significant role in human MC migration.
- ADAM 15's metalloproteinase activity is essential for this migration.
- ADAM 15 may be involved in mesangial matrix remodeling during kidney disease.