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Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging
Shi Fang Yan1, Ravichandran Ramasamy, Ann Marie Schmidt
1Department of Surgery, Columbia University, New York, NY 10032, United States.
Abstract:
The multi-ligand Receptor for Advanced Glycation Endproducts (RAGE) is implicated in the pathogenesis and progression of chronic diseases such as diabetes and immune/inflammatory disorders. Recent studies are uncovering the precise mechanisms by which distinct RAGE ligands bind the extracellular (soluble) domain of the receptor at the V-, C1- and/or C2-immunoglobulin like domains. Experiments using soluble RAGE in animals as a ligand decoy have illustrated largely beneficial effects in reducing vascular and inflammatory stress and, thereby, preventing long-term tissue damage in models of diabetes and immune/inflammatory disorders. Measurement of soluble RAGE levels in the human, both "total" soluble RAGE and a splice variant-derived product known as endogenous secretory or esRAGE, holds promise for the identification of potential therapeutic targets and/or biomarkers of RAGE activity in disease. In this article, we review the evidence from the rodent to the human implicating RAGE in the diverse disease states in which its ligands accumulate.
Insights
The Receptor for Advanced Glycation Endproducts (RAGE) pathway is crucial in chronic diseases. Soluble RAGE (sRAGE) shows therapeutic promise by acting as a decoy, reducing inflammation and tissue damage in various conditions.
Area of Science:
- Biochemistry
- Immunology
- Pathophysiology
Background:
- The multi-ligand Receptor for Advanced Glycation Endproducts (RAGE) is a key player in chronic diseases like diabetes and inflammatory disorders.
- Distinct RAGE ligands interact with specific domains (V, C1, C2) of the receptor's extracellular soluble domain.
Purpose of the Study:
- To review evidence implicating RAGE in diverse disease states.
- To explore the therapeutic potential of soluble RAGE (sRAGE) as a ligand decoy.
- To discuss the utility of measuring sRAGE and endogenous secretory RAGE (esRAGE) as biomarkers.
Main Methods:
- Review of existing scientific literature and experimental data from rodent and human studies.
- Analysis of mechanisms of RAGE ligand binding to the soluble receptor domain.
- Examination of outcomes from animal models using sRAGE as a ligand decoy.
Main Results:
- Soluble RAGE administration in animal models demonstrated beneficial effects in reducing vascular and inflammatory stress.
- These effects translated to prevention of long-term tissue damage in models of diabetes and immune/inflammatory disorders.
- Measurement of total sRAGE and esRAGE in humans shows potential for identifying therapeutic targets and biomarkers.
Conclusions:
- RAGE signaling is significantly implicated in the pathogenesis and progression of multiple chronic diseases.
- Soluble RAGE (sRAGE) exhibits therapeutic potential as a decoy, mitigating disease-associated stress and damage.
- sRAGE and esRAGE levels serve as promising biomarkers for RAGE activity and potential therapeutic intervention in human diseases.
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