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Amyloid beta 2-microglobulin is modified with imidazolone, a novel advanced glycation end product, in
T Niwa1, T Katsuzaki, S Miyazaki
1Nagoya University Branch Hospital, Japan.
Abstract:
We have recently demonstrated by immunohistochemistry that amyloid beta 2-microglobulin (beta 2m) is modified with advanced glycation end products (AGEs) in dialysis-related amyloidosis (DRA). To further investigate the role of the Maillard reaction in the pathogenesis of DRA, we produced a monoclonal antibody to imidazolone, a novel AGE, and a reaction product of arginine and 3-deoxyglucosone (3-DG) which was accumulated in uremic serum. Then we determined the localization of imidazolone in the amyloid tissues by immunohistochemistry using the antibody. The connective tissues in carpal tunnel and ligamentum flavum were obtained from six patients with carpal tunnel syndrome and two patients with destructive spondyloarthropathy. Imidazolone was localized to all the beta 2m-positive amyloid deposits in these patients. Western blotting using the antibody demonstrated that beta 2m extracted from the synovium amyloid of hemodialysis patients was modified with imidazolone. Further, beta 2m isolated from the blood ultrafiltrate of hemodialyzed patients was also modified with imidazolone. In vitro incubation of beta 2m with 3-DG produced imidazolone-modified beta 2m. In conclusion, amyloid tissue beta2m is modified with imidazolone in patients with DRA. 3-DG accumulating in uremic serum may be involved in the modification of beta 2m with imidazolone.
Insights
Dialysis-related amyloidosis (DRA) involves beta 2-microglobulin (beta 2m) modified with advanced glycation end products (AGEs). Imidazolone, a novel AGE, modifies beta 2m in DRA patients, potentially linked to 3-deoxyglucosone (3-DG) in uremic serum.
Area of Science:
- Nephrology
- Biochemistry
- Pathology
Background:
- Dialysis-related amyloidosis (DRA) is characterized by amyloid deposition of beta 2-microglobulin (beta 2m).
- Advanced glycation end products (AGEs) are implicated in the pathogenesis of various chronic diseases.
- The Maillard reaction, leading to AGE formation, is a potential contributor to DRA.
Purpose of the Study:
- To investigate the role of the Maillard reaction in DRA pathogenesis.
- To determine the presence and localization of imidazolone, a novel AGE, in DRA-associated amyloid tissues.
- To explore the modification of beta 2m by imidazolone in patients undergoing hemodialysis.
Main Methods:
- Production of a monoclonal antibody specific to imidazolone.
- Immunohistochemical analysis of connective tissues from patients with DRA.
- Western blotting to detect imidazolone modification of beta 2m in patient samples and in vitro.
- In vitro incubation of beta 2m with 3-deoxyglucosone (3-DG).
Main Results:
- Imidazolone was localized to beta 2m-positive amyloid deposits in carpal tunnel and ligamentum flavum tissues.
- Western blotting confirmed imidazolone modification of beta 2m in synovial amyloid and blood ultrafiltrate from hemodialysis patients.
- In vitro experiments demonstrated that 3-DG modifies beta 2m to form imidazolone.
Conclusions:
- Beta 2-microglobulin in amyloid tissues of DRA patients is modified with imidazolone.
- 3-Deoxyglucosone (3-DG), which accumulates in uremic serum, may be responsible for the imidazolone modification of beta 2m.
- These findings highlight the role of AGEs in the pathogenesis of dialysis-related amyloidosis.