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436


Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling

Xue, Jing; Manigrasso, Michaele; Scalabrin, Matteo; Rai, Vivek; Reverdatto, Sergey; Burz, David S; Fabris, Daniele; Schmidt, Ann Marie; Shekhtman, Alexander
The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to characterize structurally due to the large sizes of and transient interactions between monomers. The receptor for advanced glycation end products (RAGE), a signaling molecule central to the induction and perpetuation of inflammatory responses, is a weak constitutive oligomer. The RAGE domain interaction surfaces that mediate homo-dimerization were identified by combining segmental isotopic labeling of extracellular soluble RAGE (sRAGE) and nuclear magnetic resonance spectroscopy with chemical cross-linking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head to head forming an asymmetric dimer with the C termini directed toward the cell membrane. Ligand-induced association of RAGE homo-dimers on the cell surface increases the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and activating signaling pathways.
PMCID:5014727
PMID: 27524199
ISSN: 1878-4186
CID: 2219272

Soluble Levels of Receptor for Advanced Glycation Endproducts (RAGE) and Progression of Atherosclerosis in Individuals Infected with Human Immunodeficiency Virus: ACTG NWCS 332

Danoff, Ann; Kendall, Michelle A; Currier, Judith S; Kelesidis, Theodoros; Schmidt, Ann Marie; Aberg, Judith A
Identification of biomarkers and/or mediators of cardiovascular disease (CVD) associated with HIV infection would be of diagnostic and therapeutic value. As soluble receptor for advanced glycation endproducts (sRAGE) and endogenous secretory (esRAGE) have been implicated in vascular complications in other settings, we investigated whether either soluble form of RAGE was associated with changes in carotid intima-media thickness (CIMT) in HIV-infected patients and HIV-uninfected controls. We found no differences in sRAGE, esRAGE, or CIMT among groups at study entry, or in yearly rates of change in sRAGE, esRAGE, or CIMT by HIV-serostatus (all p > 0.10). However, yearly rates of change in sRAGE (p = 0.07) and esRAGE (p < 0.001) were higher in those taking protease inhibitors, and lower baseline esRAGE levels (p = 0.06) were associated with increased odds of CIMT progression in HIV-infected individuals. Although esRAGE was not altered by HIV-serostatus (p = 0.17), its inverse relationship with CIMT progression in HIV-infected patients suggests a possible role as a mediator of CVD in HIV-infected persons.
PMCID:5053332
PMID: 27216802
ISSN: 1573-2576
CID: 2114922

Complying With the National Institutes of Health Guidelines and Principles for Rigor and Reproducibility: Refutations

Daugherty, Alan; Hegele, Robert A; Mackman, Nigel; Rader, Daniel J; Schmidt, Ann Marie; Weber, Christian
PMID: 27335467
ISSN: 1524-4636
CID: 2158082

Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics

Abedini, Andisheh; Plesner, Annette; Cao, Ping; Ridgway, Zachary; Zhang, Jinghua; Tu, Ling-Hsien; Middleton, Chris T; Chao, Brian; Sartori, Daniel; Meng, Fanling; Wang, Hui; Wong, Amy G; Zanni, Martin T; Verchere, C Bruce; Raleigh, Daniel P; Schmidt, Ann Marie
Islet amyloidosis by IAPP contributes to pancreatic beta-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 beta-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive beta-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced beta-cell death.
PMCID:4940161
PMID: 27213520
ISSN: 2050-084x
CID: 2114872

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Belmokhtar, Karim; Robert, Thomas; Ortillon, Jeremy; Braconnier, Antoine; Vuiblet, Vincent; Boulagnon-Rombi, Camille; Diebold, Marie Daniele; Pietrement, Christine; Schmidt, Ann Marie; Rieu, Philippe; Toure, Fatouma
OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. APPROACH AND RESULTS: We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of alpha-SMA. Ager transcript levels in the aorta were 6x higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. CONCLUSIONS: Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE.
PMID: 26988587
ISSN: 1524-4636
CID: 2572612

Aldose Reductase Acts as a Selective Derepressor of PPARgamma and the Retinoic Acid Receptor

Thiagarajan, Devi; Ananthakrishnan, Radha; Zhang, Jinghua; O'Shea, Karen M; Quadri, Nosirudeen; Li, Qing; Sas, Kelli; Jing, Xiao; Rosario, Rosa; Pennathur, Subramaniam; Schmidt, Ann Marie; Ramasamy, Ravichandran
Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of the nuclear receptor corepressors NCOR1 and SMRT for its stability and activity. Here, we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARgamma signaling, resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent derepression of PPARgamma and RAR.
PMCID:4826833
PMID: 27052179
ISSN: 2211-1247
CID: 2066152

Deletion of the formin, DRF1, is protective against renal damage in a murine model of diabetes [Meeting Abstract]

Manigrasso, M B; Rosario, R; Ramasamy, R; D'Agati, V; Schmidt, A M
Our studies have shown the cytoplasmic domain of the receptor for advanced glycation endproducts (RAGE) binds to the formin molecule, diaphanous-1 (mDia1). mDia1 is a member of the formin family of intracellular molecules involved in cellular migration which act as effectors of Rho GTPase signaling. In RAGE-expressing cells devoid of Drf1 (gene encoding mDia1), incubation with RAGE ligands failed to generate reactive oxygen species or activate key signaling cellular stress pathways. Here, we sought to determine if mDia1 plays key roles in a murine model of diabetic nephropathy (DN). Our preliminary data reveal that mDia1 expression is increased in human and murine diabetic podocytes and parietal epithelial cells in a diffuse and global pattern compared to age-matched controls. Furthermore, expression patterns of mDia1 are highly analogous to those of RAGE. While the role of RAGE has been shown to play a key role in the development of DN, the potential contribution of mDia1 has yet to be elucidated. Therefore, we tested the hypothesis that mDia1 contributes to the development and progression of diabetic renal disease in a murine model. Male wild-type and Drf1-null (WT, Drf1KO; all in the C57BL/6 background) mice were rendered diabetic at 6 weeks of age with streptozotocin and sacrificed after 3 or 6 months of diabetes. Kidneys were harvested and processed for histology and gene expression and stained with periodic-acid Schiff (PAS) and semi-quantitative scoring was used to determine the degree of mesangial sclerosis by average findings in >100 glomeruli/mouse (scale 0-3+; 0=absent, 1=mild, 2=moderate, 3=severe). Glomerular basement membrane (GBM) thickness and podocyte foot process effacement (FPE) were measured by ultrastructural analysis (>8 glomeruli/mouse). Gene expression of inflammatory markers (transforming growth factor beta; Tgfb, interleukin 6; Il6, and monocyte chemoattractant protein 1; Ccl2) were assessed by quantitative real time PCR using RNA prepared from whole kidney cortex and normalized to beta-actin. This preliminary study suggests that deletion of Drf1 in mice results in a substantial protection against indices of DN by reducing podocyte effacement, inflammation and fibrosis in type 1 DM. View this table: In this window In a new window Table 1 Histological and microscopic observations show that mDiaKO mice have a reduced GBM, less podocyte FPE and a decrease in mesangial sclerosis compared to WT mice after 6 months of diabetes. (Table Presented)
EMBASE:72321370
ISSN: 1530-6860
CID: 2167522

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie
The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).
PMCID:4776135
PMID: 26936329
ISSN: 2045-2322
CID: 2006392

Role of the receptor for advanced glycation end products (RAGE) in intestinal fibrosis [Meeting Abstract]

Speca, S; Body-Malapel, M; Djouina, M; Boulanger, E; Schmidt, A -M; Desreumaux, P; Vignal, C
Background: Intestinal fibrosis is a common and severe complication of inflammatory bowel disease (IBD) characterized by excessive deposition of extracellular matrix components (ECM). Inflamed colonic mucosa of patients with active IBD shows a significant increase in expression of the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily of cell surface receptors. Several evidences in kidney, liver and lung fibrosis show how the increased myofibroblast activation and the consequent ECM accumulation are regulated by RAGE. Aim of this study is to investigate the involvement of RAGE i) in in vitro differentiation of human colonic fibroblasts (CCD-18 Co) and epithelial cells (HT29) into myofibroblasts and ii) in the development of the DSS-induced intestinal fibrosis in mice. Methods: Differentiation of CCD-18 Co and HT29 into myofibro-blasts was induced by 4 day of TGF-beta administration (1ng/mL and 10 ng/mL, respectively). Expression of alpha-SMA (ACTA2) gene and fibronectin (Fn-1) gene, as well as RAGE was measured by quantitative RT-PCR. Chronic colonic fibrosis was induced in C57BL/6 mice by successive 2,5% (w/v) DSS administration in drinking water for 6 weeks. After 6 weeks main parameters associated to a pro-fibrotic profile were assessed macroscopically (weight/length of the colon, edema, ulcers, adhesions, thickness, dilatation), histologically (inflammatory infiltrate, collagen deposition) and biologically (Tgf-beta1, Col1A1 and Fn-1 gene expression) Results: TGF-beta-induced myofibroblast activation was associated to a significant increase in the ACTA2 expression (65%, p< 0.01 for CCD-18 Co and 183.8%, p< 0.001 for HT29) and mRNA Fn-1 levels (75.5%, p<0.001 in CCD-18 Co and 122%, p< 0.001, in HT29) and correlated with a significant RAGE upregulation both in CCD-18 Co and HT29 (48%, p<0.005 and 1.47%, p<0.005, respectively). RAGE-/- mice showed a significant 23.8% decrease of total macroscopic score and 49% decrease of total microscopic score compared to WT mice. mRNA Tgf-beta1 expression was significantly increased 3.4 fold by the DSS administration in WT mice colon, whereas it was unchanged in RAGE null mice compared to mice receiving only tap water. Col1A1 and Fn-1 genes were upregulated in DSS-treated WT mice (5.52 folds, p= 0.137 and 53 folds, p= 0.0016, respectively). Lack of RAGE decreased 3.17 folds (p= 0.0341) Col1A1 expression and totally prevents the Fn-1 upregulation induced by DSS treatment Conclusions: The potential pro-fibrotic RAGE properties in IBD represent a new frontier for a better understanding of the mechanisms related to intestinal fibrosis and for the development of new therapeutic approaches
EMBASE:71994404
ISSN: 1873-9946
CID: 1796952

Rage Contributes To Particulate-Induced Lung Function Loss And Hyperreactivity: Mitigating The Persistent Effects Of A Single Intense Particulate Exposure [Meeting Abstract]

Kwon, S; Haider, SH; Caraher, EJ; Crowley, G; Lee, AK; Ebrahim, M; Prezant, DJ; Schmidt, A; Nolan, A
ISI:000390749607452
ISSN: 1535-4970
CID: 2414982