Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders

doi:10.1016/j.abb.2003.08.030

Archives of Biochemistry and Biophysics

Volume 419, Issue 1, 1 November 2003, Pages 80-88

https://doi.org/10.1016/j.abb.2003.08.030 Get rights and content

Abstract

The glycation and oxidation of proteins/lipids leads to the generation of a new class of biologically active moieties, the advanced glycation endproducts (AGEs). Recent studies have elucidated that carboxymethyllysine (CML) adducts of proteins/lipids are a highly prevalent AGE in vivo. CML-modified adducts are signal transduction ligands of the receptor for AGE (RAGE), a member of the immunoglobulin superfamily. Importantly, CML-modified adducts accumulate in diverse settings. In addition to enhanced formation in settings of high glucose, these adducts form in inflammatory milieu. Studies performed both in vitro and in vivo have suggested that the proinflammatory/tissue destructive consequences of RAGE activation in the diabetic/inflamed environment may be markedly attenuated by blockade of the ligand–RAGE axis. Here, we will summarize the known consequences of RAGE activation in the tissues and highlight novel areas for therapeutic intervention in these disease states.

Section snippets

Glycoxidation products: formation and pathologic consequences

Advanced glycation endproducts (AGEs)¹ are an heterogeneous class of modified adducts that form in multiple settings, including such

Receptor for AGE: a receptor of the immunoglobulin superfamily

RAGE was identified as a cellular interaction site for AGEs based on radioligand-binding studies in a range of cultured cells linked to diabetes-associated complications. For example, AGEs, either those prepared in vitro such as AGE-modified bovine serum albumin, or those retrieved/purified directly from in vivo sources, such as urine or peritoneal dialysis fluid from diabetic subjects, were found to interact with endothelial cells (EC), peripheral blood-derived monocytes (MP), and vascular

RAGE: patterns of expression

Multiple studies have shown that in homeostasis, RAGE is expressed at low levels in the adult in a range of cell types, such as EC, MP, lymphocytes, VSMC, glomerular epithelial cells or podocytes, and neurons [30], [31], [32], [33]. However, in embryonic development, RAGE expression is increased in the developing neurons of the central nervous system; immunohistochemical and in situ hybridization studies identified enhanced RAGE expression in neurons of the developing cerebral cortex,

RAGE is a multi-ligand receptor

Although RAGE was first identified as a receptor for AGEs, it became apparent that beyond AGEs, the receptor was capable of engaging distinct ligands beyond biochemically modified species (Table 1). Our studies have shown that in addition to AGEs, RAGE is a signal transduction ligand for amyloid-β peptide (Aβ) and β-sheet fibrils that form in amyloidoses [36], [38], [39]; amphoterin and S100/calgranulins.

Amphoterin is a member of the high mobility group (HMG)-1 family of DNA-binding proteins.

RAGE and enhanced vascular permeability in diabetes

Increased vascular leakage is a well-known feature of diabetic microvasculature and may be studied in rodent models of diabetes [51], [52], [53]. To address the role of RAGE in this setting, we induced diabetes in rats using streptozotocin. By 11 weeks after administration of streptozotocin in the setting of persistent hyperglycemia, diabetic animals displayed increased vascular leakage, as demonstrated by the tissue-blood isotope ratio (TBIR) [53]. Increased vascular permeability in diabetic

RAGE and other diabetic complications

In addition to macrovascular disease, other complications of diabetes are important contributors to the increased morbidity observed in affected populations. Our laboratory has studied the role of ligand–RAGE activation in a number of complications of diabetes thus far; in each case, a role for this axis seems to exist suggesting that in these distinct settings, RAGE blockade may be a feasible therapeutic strategy.

Genetic variants of RAGE: polymorphisms and potential implications

Lastly, it is established that an important factor likely to impact on the design of clinical trials is the degree to which individuals may display enhanced/reduced predisposition for the development of diabetic complications based on variants in key genes involved in initiation and/or progression of the disease. A number of studies have now reported genetic variants of RAGE, both within the coding/translated region, as well as within transcriptional regulatory elements [69], [70], [71], [72].

Conclusions and perspectives

The observation that RAGE is a multi-ligand member of the immunoglobulin superfamily has led to the appreciation that the molecule may be involved in a broad array of disease settings in which these ligands accumulate. In our animal model systems studied to date, AGEs and S100/calgranulins accumulate to enhanced degrees in diabetic tissues as well as in inflamed foci; blockade of the receptor in vivo in those situations suggests that a beneficial response may be achieved by RAGE blockade.

Acknowledgements

This work was funded in part by the Surgical Research Fund, grants from the U.S. P.H.S., Juvenile Diabetes Research Foundation International, American Heart Association, LeDucq Foundation, and the Burroughs Wellcome Fund. A.M.S. is a recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

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MinireviewBlockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders

Abstract

Section snippets

Glycoxidation products: formation and pathologic consequences

Receptor for AGE: a receptor of the immunoglobulin superfamily

RAGE: patterns of expression

RAGE is a multi-ligand receptor

RAGE and enhanced vascular permeability in diabetes

RAGE and other diabetic complications

Genetic variants of RAGE: polymorphisms and potential implications

Conclusions and perspectives

Acknowledgements

J. Diabetes Complications

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

TIBS

Brain Res. Bull.

Int. J. Biochem. Cell Biol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Am. J. Pathol.

Clin. Plast. Surg.

Am. J. Pathol.

Lung Cancer

Annu. Rev. Med.

Proc. Natl. Acad. Sci. USA

J. Clin. Invest.

J. Neurosci.

Biochemistry

Biochemistry

Biochem. J.

J. Clin. Invest.

J. Clin. Invest.

Biochem. Soc. Trans.

Contrib. Nephrol.

Clin. Nephrol.

J. Clin. Invest.

J. Clin. Invest.

J. Clin. Invest.

Minireview
Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders