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Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and
Szu-Yuan Li1, Po-Hsun Huang2, An-Hang Yang3
1Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Abstract:
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.
Insights
Matrix metalloproteinase-9 (MMP-9) contributes to diabetic nephropathy by increasing extracellular matrix deposition and podocyte damage. Inhibiting MMP-9 in diabetic mice reduced kidney damage, suggesting MMP-9 as a potential therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Diabetic nephropathy involves excessive extracellular matrix deposition and glomerular filtration barrier disruption.
- Altered matrix metalloproteinases (MMPs) expression, particularly MMP-9, is implicated in diabetic nephropathy pathogenesis.
- Understanding MMP-9's role is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of matrix metalloproteinase-9 (MMP-9) in diabetic nephropathy.
- To evaluate the therapeutic potential of targeting MMP-9 in a diabetic nephropathy mouse model.
- To examine MMP-9 expression and function in diabetic patient samples.
Main Methods:
- Utilized a streptozotocin-induced diabetic mouse model with MMP-9 gene knockout.
- Conducted in vitro experiments using cultured podocytes stimulated with diabetic nephropathy-related cytokines.
- Analyzed clinical samples from diabetic patients, assessing urinary MMP-9 levels.
- Employed gelatin zymography and western blotting to assess MMP-9 activity and production.
Main Results:
- Diabetic mice exhibited increased albuminuria, kidney hypertrophy, and glomerular basement membrane thickening.
- Mice lacking MMP-9 showed significantly attenuated diabetic nephropathy markers.
- In vitro, cytokines stimulated MMP-9 secretion, leading to podocyte dedifferentiation and increased permeability.
- Urinary MMP-9 levels were elevated in diabetic patients before microalbuminuria onset.
Conclusions:
- Matrix metalloproteinase-9 (MMP-9) plays a significant role in the development and progression of diabetic nephropathy.
- MMP-9 contributes to podocyte injury, extracellular matrix accumulation, and impaired kidney function.
- Elevated urinary MMP-9 may serve as an early biomarker for diabetic nephropathy.
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