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High glucose reduces generation of plasmin activity by mesangial cells
E J Fisher1, S V McLennan, D K Yue
1Department of Medicine, University of Sydney, New South Wales, Australia.
Abstract:
Mesangium enlargement is a central feature of diabetic nephropathy and almost certainly plays a pathogenic role in this condition. Previous studies have shown that mesangium degradation is reduced in a high glucose mileau. Plasmin has been shown to play an important role in extracellular matrix degradation, both directly and through its ability to activate the matrix metalloproteinases. We therefore investigated how high glucose concentration may affect the various components of the plasminogen cascade on mesangial cells and whether it impairs the ability of the mesangial cell to generate plasmin activity. Result showed decreased binding of plasminogen and the urokinase type plasminogen activator to the mesangial cell surface while the tissue type plasminogen activator and the plasminogen activator-1 associated with mesangial cells were increased. The net effect of these changes was a reduced capacity of mesangial cell layers to generate plasmin activity in a high glucose environment. We postulate that this may be of importance in the reduced mesangium degradation which occurs in diabetes.
Insights
High glucose impairs mesangial cell function in diabetic nephropathy by reducing plasmin generation. This contributes to decreased extracellular matrix degradation, a key factor in kidney disease progression.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Mesangial enlargement is a hallmark of diabetic nephropathy.
- Reduced mesangium degradation occurs in high glucose environments.
- Plasmin is crucial for extracellular matrix degradation.
Purpose of the Study:
- To investigate the effect of high glucose on the plasminogen cascade in mesangial cells.
- To determine if high glucose impairs mesangial cell plasmin generation.
Main Methods:
- Cultured human mesangial cells were exposed to high glucose concentrations.
- Analysis of plasminogen cascade components (plasminogen, urokinase-type plasminogen activator, tissue-type plasminogen activator, plasminogen activator inhibitor-1) on cell surface and associated with cells.
- Measurement of mesangial cell plasmin activity generation.
Main Results:
- High glucose decreased plasminogen and urokinase-type plasminogen activator binding to mesangial cells.
- High glucose increased tissue-type plasminogen activator and plasminogen activator inhibitor-1 associated with mesangial cells.
- Overall reduction in mesangial cell plasmin activity generation under high glucose conditions.
Conclusions:
- High glucose significantly alters the plasminogen cascade on mesangial cells.
- This alteration leads to reduced plasmin generation capacity in a high glucose milieu.
- The impaired plasmin activity may explain reduced mesangium degradation in diabetic nephropathy.