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Ribozyme targeting of receptor for advanced glycation end products in mouse mesangial cells
1Department of Geriatric Medicine, Faculty of Medicine, Kyoto University, Japan.
Abstract:
Accumulation of extracellular matrix is a characteristic of diabetic nephropathy, and advanced glycation end products (AGEs) are considered to play an important role in the mechanism. To investigate the involvement of the receptor for AGE (RAGE) in upregulation of type IV collagen by AGEs, we applied the hammerhead ribozyme for targeting RAGE. We established a stable mouse mesangial cell line that produces the RAGE-specific ribozyme (Rz-RAGE). Both the RAGE mRNA and protein were decreased in the cell line. The amount of type IV collagen mRNA increased by AGEs' treatment in control cells. In contrast, the increase of type IV collagen induced by AGEs was not observed in the Rz-RAGE-producing cells. We conclude that the induction of type IV collagen by AGEs is mediated by RAGE and this mechanism could be involved in diabetic nephropathy. This study also suggested the experimental/therapeutic potential of hammerhead ribozymes.
Insights
Advanced glycation end products (AGEs) increase type IV collagen in diabetic nephropathy via the receptor for AGE (RAGE). Targeting RAGE with ribozymes blocked this increase, suggesting RAGE
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Diabetic nephropathy is characterized by extracellular matrix accumulation.
- Advanced glycation end products (AGEs) are implicated in diabetic nephropathy pathogenesis.
- The receptor for AGE (RAGE) is a key mediator in AGEs' signaling pathways.
Purpose of the Study:
- To investigate the role of RAGE in AGEs-induced upregulation of type IV collagen.
- To explore the potential of hammerhead ribozymes in targeting RAGE for therapeutic purposes.
Main Methods:
- Established a stable mouse mesangial cell line producing a RAGE-specific hammerhead ribozyme (Rz-RAGE).
- Quantified RAGE mRNA and protein levels in Rz-RAGE cells.
- Assessed type IV collagen mRNA expression following AGEs treatment in control and Rz-RAGE cells.
Main Results:
- Rz-RAGE cells exhibited significantly reduced RAGE mRNA and protein expression.
- AGEs treatment increased type IV collagen mRNA in control cells.
- AGEs-induced type IV collagen upregulation was abolished in Rz-RAGE cells.
Conclusions:
- AGEs-induced type IV collagen production is mediated through RAGE.
- RAGE-mediated collagen synthesis is a potential mechanism in diabetic nephropathy.
- Hammerhead ribozymes demonstrate potential as experimental and therapeutic tools for targeting RAGE.
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