The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

This is the published version. Copyright 2001 American Society for Clinical Investigation.The multiligand receptors that form the focus of this Perspective series have expectedly diverse functions, often conforming to potential gaps in the host response to invading pathogens that are not effectively manned by adaptive immunity. For example, the macrophage scavenger receptor (type A) interacts with bacterial cell walls and enhances clearance of Gram-negative bacteria from the circulation (1). Similarly, the macrophage mannose receptor binds mannose-rich carbohydrates typical of many microorganisms, thereby promoting their cellular uptake and disposal (2). The present contribution to the series concerns a member of the immunoglobulin superfamily that differs from the above molecules in that all known ligands in its broad repertoire can be generated endogenously (3). This cell surface protein, called RAGE because it serves as a receptor for nonenzymatically glycated adducts termed “advanced glycation endproducts” (AGEs), also binds β-sheet fibrils characteristic of amyloid; proinflammatory cytokine–like mediators of the S100/calgranulin family; and amphoterin, a nuclear protein sometimes found in the ECM (Table 1). Binding of these ligands to RAGE does not accelerate clearance or degradation but rather begins a sustained period of cellular activation mediated by receptor-dependent signaling. This is the first of several distinctive themes that have emerged from studies of RAGE. Other unusual features of the receptor include its ability to engage classes of molecules, rather than individual ligands, and its enhanced surface expression in environments rich in RAGE ligands. This last point is crucial, since it explains how upregulation of this receptor can contribute to an ascending spiral of RAGE-dependent cellular perturbation. Taken together, these features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues. As described below, these diverse situations range from the complications of diabetes and cellular perturbation in amyloidoses to immune and inflammatory responses and tumor cell behavior

Reductive Metabolism of AGE Precursors: A Metabolic Route for Preventing AGE Accumulation in Cardiovascular Tissue

OBJECTIVE—To examine the role of aldo-keto reductases (AKRs) in the cardiovascular metabolism of the precursors of advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS—Steady-state kinetic parameters of AKRs with AGE precursors were determined using recombinant proteins expressed in bacteria. Metabolism of meth-ylglyoxal and AGE accumulation were studied in human umbil-ical vein endothelial cells (HUVECs) and C57 wild-type, akr1b3 (aldose reductase)-null, cardiospecific-akr1b4 (rat aldose reduc-tase), and akr1b8 (FR-1)-transgenic mice. AGE accumulation and atherosclerotic lesions were studied 12 weeks after streptozoto-cin treatment of C57, akr1b3-null, and apoE- and akr1b3-apoE– null mice. RESULTS—Higher levels of AGEs were generated in the cytosol than at the external surface of HUVECs cultured in high glucose

Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al

Overexpression of receptor of advanced glycation end products hypersensitizes cells for amyloid beta peptide-induced cell death

Hadding A, Kaltschmidt B, Kaltschmidt C. Overexpression of receptor of advanced glycation end products hypersensitizes cells for amyloid beta peptide-induced cell death. Biochim Biophys Acta. 2004;1691(1):67-72