The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease

Abstract

Introduction: This review focuses on the multi-ligand receptor of the immunoglobulin superfamily--receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging.

Areas covered: In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; and tumors and Alzheimer's disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule--the formin DIAPH1. Physicochemical evidence of how the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences thereof, are also reviewed.

Expert opinion: We discuss the modalities of RAGE antagonism currently in preclinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging wherein RAGE ligands accumulate and signal.

Keywords: alzheimer’s disease; diabetes; inflammation; neurodegeneration; obesity; receptor.

Figure 1. Deletion of Ager suppresses diabetes-accelerated atherosclerosis and effect of diabetes and Ager deficiency on macrophage and smooth muscle cell lesional content

(a). Male Apoe null and Apoe null/Ager null mice were rendered diabetic with streptozotocin at age 6 weeks. Mice were sacrificed and aortas were retrieved. Mean atherosclerotic lesion area at the aortic sinus is shown. (b). Immunostaining and Picrosirius Red staining of atherosclerotic lesions from the indicated Apoe null mice was performed for detection of macrophages, smooth muscle cells, T cells and collagen per lesion area (the latter using picrosirius red and polarizing microscopy) at age 24 weeks. Statistical considerations: * indicates p<0.03 vs. Apoe null/Ager null diabetic mice; ** indicates p<0.01 vs. Apoe null/Ager null diabetic mice; and ^ indicates p<0.02 vs. Apoe null/Ager null non-diabetic mice. Adapted from Circ Res 2010;106:1040–1051.

Figure 2. Effect of Ager or/and Myd88 gene deletion on survival after extensive (85%) hepatectomy

Kaplan-Meier curves for Wild-type (WT), Ager null, Myd88 null, or Myd88 / Ager null mice were plotted, and the statistical significance of the probability of survival of the mutants vs. WT mice was calculated. n = 10 mice/group. Statistical considerations: Ager−/− vs. WT, P = 0.01; Ager−/− vs. Myd88−/−, P < 0.001; Myd88−/− vs. WT, P = 0.013; Myd88−/− vs. Myd88−/−/Ager−/−, P = 0.144. Adapted from FASEB J 2012; 26: 882–893.

Figure 3. Cytoplasmic tail (ct)RAGE interacts with DIAPH1 FH1 domain

(a). Sequence alignment of the human DIAPH1 FH1 construct used in this study (NCBI accession code NP_005210) and mouse DIAPH1 FH1 (NCBI accession code NP_031884). Conserved residues are in red. (b). Overlay of ¹⁵N-edited heteronuclear single quantum coherence, HSQC, NMR spectra of free [U-¹⁵N] ctRAGE (black) and the DIAPH1 FH1-[U-¹⁵N]ctRAGE complex (red). To form the DIAPH1 FH1-ctRAGE complex, 0.5 mM unlabeled DIAPH1 FH1, in NMR buffer (10 mM potassium phosphate (pH 6.5), 100 mM NaCl, 0.02% (w/v) NaN₃, in 90%/10% H2O/D2O) was added into 100 µM [U-¹⁵N]ctRAGE to yield a DIAPH1 FH1/ctRAGE molar ratio of 1:1. Due to ¹⁵N editing of the experiment, only backbone and side chain amide protons and nitrogens of ctRAGE are present in the spectrum. Most peaks do not change their positions, reflecting the fact that only a subset of ctRAGE residues interact with FH1. ctRAGE peaks that are substantially or completely broadened are labeled. Note that Q3, R4, R5, and Q6 of ctRAGE correspond to Q364, R365, R366 and Q367 of the full length RAGE (c). DIAPH1 FH1-ctRAGE interaction map. Residues broadened during the NMR titration experiment are indicated in red. J Biol Chem 2012; 287:5133–5144.

Figure 4. RAGE & regulation of ligand levels

Content of two of the classes of RAGE ligands, glyoxal (G) and methylglyoxal (MG)-derived AGEs, and amyloid-β-peptide (Aβ), may be regulated, in part, by RAGE, in chronic disease settings. First, in the case of AGEs, the key pre-AGE intermediates, G and MG, are detoxified by the enzyme glyoxalase 1 (GLO1). Published evidence indicates that RAGE downregulates Glo1 mRNA and activity in certain diabetic tissues. Hence, RAGE activation in high-AGE settings may stimulate AGE production and accumulation via a feed-forward loop in which RAGE suppresses the brake on pre-AGE (G & MG) detoxification, thereby favoring more conversion into AGEs. These considerations have implications for conditions such as diabetes complications. Second, in the case of Aβ, published evidence suggests that ligand-RAGE interaction might upregulate BACE1, thereby promoting further production of Aβ. These considerations have implications for conditions such as Alzheimer’s disease. Abbreviations: AGE, advanced glycation endproduct; G, glyoxal; GLO1, glyoxalase 1; and MG, methylglyoxal.