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Pathophysiology of advanced glycation end-products in renal failure
1Department of Internal Medicine, Branch Hospital, Nagoya University School of Medicine, Japan.
Abstract:
beta 2-Microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis, a serious complication leading to bone and joint destruction in long-term haemodialysis patients. However, the molecular pathogenesis of this complication remains unknown. Intact beta 2-microglobulin per se seems an unlikely contributor to the pathogenesis, because no difference in the plasma levels of intact beta 2-microglobulin has yet been found between haemodialysis patients with and without this complication. Some investigators have therefore focused on the modification of this molecule. Recent studies have revealed a new modification of beta 2-microglobulin in amyloid fibrils-the advanced glycation end-products (AGEs) formed by a non-enzymatic reaction between sugar aldose and protein. Further studies have suggested that the interaction of AGE-modified beta 2-microglobulin with monocyte/macrophage and osteoclast/osteoblast gives a plausible albeit partial explanation for the mechanism of bone and joint destruction in dialysis-related amyloidosis. This article discusses the pathophysiology of AGEs in renal failure and the modification of beta 2-microglobulin with AGEs, especially focusing on their structure and pathological role in dialysis-related amyloidosis.
Insights
Advanced glycation end-products (AGEs) modify beta 2-microglobulin, contributing to bone and joint destruction in dialysis-related amyloidosis. This AGE modification offers a partial explanation for the disease
Area of Science:
- Nephrology
- Biochemistry
- Pathology
Background:
- Dialysis-related amyloidosis (DRA) causes bone and joint destruction in long-term hemodialysis patients.
- The molecular pathogenesis of DRA is not fully understood.
- Intact beta 2-microglobulin levels do not differ between patients with and without DRA, suggesting molecular modification is key.
Purpose of the Study:
- To discuss the pathophysiology of advanced glycation end-products (AGEs) in renal failure.
- To explore the modification of beta 2-microglobulin with AGEs.
- To focus on the structure and pathological role of AGE-modified beta 2-microglobulin in DRA.
Main Methods:
- Review of recent studies on beta 2-microglobulin modification in amyloid fibrils.
- Discussion of AGE formation via non-enzymatic reactions between sugars and proteins.
- Analysis of interactions between AGE-modified beta 2-microglobulin and relevant cells.
Main Results:
- Advanced glycation end-products (AGEs) are a novel modification of beta 2-microglobulin in DRA amyloid fibrils.
- AGE formation occurs through non-enzymatic glycation of proteins.
- AGE-modified beta 2-microglobulin interacts with monocytes/macrophages and osteoclasts/osteoblasts.
Conclusions:
- AGE modification of beta 2-microglobulin provides a plausible mechanism for bone and joint destruction in DRA.
- Understanding AGE pathophysiology in renal failure is crucial for DRA.
- Targeting AGE formation or its interactions may offer therapeutic strategies for DRA.