The role of the receptor for advanced glycation end-products in lung fibrosis

2007 ◽  
Vol 293 (6) ◽  
pp. L1427-L1436 ◽  
Author(s):  
Mei He ◽  
Hiroshi Kubo ◽  
Kota Ishizawa ◽  
Ahmed E. Hegab ◽  
Yasuhiko Yamamoto ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Advanced Glycation End Products ◽  
Lung Fibrosis ◽  
Alveolar Type ◽  
Type Ii ◽  
Wild Type ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end-products (RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient (RAGE−/−) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE−/− mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of the potent RAGE-inducible profibrotic cytokines transforming growth factor (TGF)-β and PDGF. In addition, bleomycin administration induced high mobility group box 1 (HMGB-1) production, one of the ligands of RAGE, from inflammatory cells that accumulated within the air space. Coculture with HMGB-1 induced epithelial-mesenchymal transition (EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE−/− mice did not respond to HMGB-1 treatment, such that the RAGE/HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced profibrotic cytokines TGF-β and PDGF only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and profibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.

scholarly journals Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury

2009 ◽  
Vol 297 (1) ◽  
pp. L1-L5 ◽  
Author(s):  
Xiao Su ◽  
Mark R. Looney ◽  
Naveen Gupta ◽  
Michael A. Matthay
Keyword(s):  
Lung Injury ◽  
Advanced Glycation End Products ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Experimental Models ◽  
Alveolar Type ◽  
Type I ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Receptor for advanced glycation end-products (RAGE) is a marker of alveolar type I cells and is elevated in the pulmonary edema fluid of patients with acute lung injury (ALI). We tested the hypothesis that RAGE in the bronchoalveolar lavage (BAL) would be elevated in experimental models of direct ALI characterized by alveolar epithelial cell injury. We developed ELISA measurements for RAGE and studied ALI (direct and indirect) mouse models and collected BAL at specified endpoints to measure RAGE. We also tested whether levels of BAL RAGE correlated 1) with the severity of lung injury in acid and hyperoxia-induced ALI and 2) with the beneficial effect of a novel treatment, mesenchymal stem cells (MSC), in LPS-induced ALI. In ALI models of direct lung injury induced by intratracheal instillation of acid, LPS, or Escherichia coli, the BAL RAGE was 58-, 22-, and 13-fold elevated, respectively. In contrast, BAL RAGE was not detectable in indirect models of ALI induced by an intraperitoneal injection of thiourea or by an intravenous injection of MHC I monoclonal antibody that produces a mouse model of transfusion-related ALI. BAL RAGE did correlate with the severity of lung injury in acid and hyperoxia-induced ALI. In addition, with LPS-induced ALI, BAL RAGE was markedly reduced with MSC treatment. In summary, BAL RAGE is an indicator of ALI, and it may be useful in distinguishing direct from indirect models of ALI as well as assessing the response to specific therapies.

Advanced glycation end-products associate with podocytopathy in type II diabetic patients

2021 ◽  
Author(s):  
Rajkishor Nishad ◽  
Tahaseen V Syed ◽  
Manga Motrapu ◽  
Rajesh Kavvuri ◽  
Kiranmayi Kodali ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Advanced Glycation End Products ◽  
Diabetic Patients ◽  
Type Ii ◽  
Advanced Glycation ◽  
Mesenchymal Transition ◽  
Glycation End Products ◽  
End Products ◽  
Carboxymethyl Lysine

Abstract Background The prevalence of diabetes reaches epidemic proportions, affecting the incidence of diabetic nephropathy (DN) and associated end-stage kidney disease (ESKD). Diabetes is the leading cause of ESKD since 30–40% of diabetic patients develop DN. Albuminuria and eGFR have been considered a surrogate outcome of chronic kidney disease, and the search for a biomarker that predicts progression to diabetic kidney disease is intense.Methods We analyzed the association of serum advanced glycation end-products (AGEs) index (AGI) with impaired kidney function in uncontrolled diabetic patients (type II, n = 130) with albuminuria ranging from (150 to 450 mg/day). The kidney biopsy specimens were also examined for the association of AGEs, particularly carboxymethyl lysine (CML) with kidney function. Further, we also assessed the effect of carboxymethyl lysine on glomerular injury and podocytopathy in experimental animals.Results We observed a strong correlation between AGI and impaired kidney function in miroalbuminuric patients with hyperglycemia. A significant association between CML levels and impaired kidney function was noticed. Administration of CML in mice showed heavy proteinuria and glomerular abnormalities. Reduced podocyte number observed in mice administered with CML could be attributed to the epithelial-mesenchymal transition (EMT) of podocytes. Conclusion Serum AGEs could be independently related to the podocyte injury vis-a-vis the risk of DN progression to ESKD in patients with microalbuminuria. AGEs or CML could be considered a prognostic marker to assess microalbuminuria progression to ESKD in diabetic patients.

scholarly journals Consumption of Dietary Advanced Glycation End Products Promotes Prostate Tumor Growth by Creating a Tumor Enhancing Stromal Microenvironment

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 359-359
Author(s):  
David Turner ◽  
Bradley Krisanits ◽  
Callan Frye ◽  
Lourdes Nogueira ◽  
Ried Schuster ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tumor Growth ◽  
Advanced Glycation End Products ◽  
Prostate Tumor ◽  
Migration And Invasion ◽  
Advanced Glycation ◽  
Neoplastic Growth ◽  
Incidence And Mortality ◽  
Glycation End Products ◽  
End Products

Abstract Objectives The literature regarding the role of advanced glycation end products (AGEs) on tumor biology has shown only moderate promise reflected by increases in cell growth, migration and invasion in vitro which is not supported by increased tumor growth in vivo14-16– A caveat to these studies is that they are centered upon a single AGE peptide and a subsequent assessment of their molecular effects on tumor epithelial cells. The objective is to show that by feeding mice a high AGE diet we can recapitulate a microenvironment comprising of a wide spectrum of AGEs which can influence neoplastic growth. Methods We recapitulated a dietary-AGE induced microenvironment in syngeneic xenograft and spontaneous breast and prostate mouse cancer models and the effects on tumor growth assessed. The mechanistic consequences of dietary-AGEs on the tumor microenvironment were further defined using mouse and human primary and immortalized two-compartment co-culture ex vivo culture models. Results Dietary-AGE consumption in breast and prostate tumor models significantly accelerated tumor growth by functioning as ligand to the transmembrane receptor for AGE (RAGE). Our studies demonstrate that AGEs promote neoplastic growth by functioning as ligand to RAGE expressed in the tumor stroma not the tumor epithelial cells. Dietary-AGE activation of RAGE in both breast and prostate tumors caused a regulatory program of ‘activated fibroblasts’ defined by increased expression of cancer associated fibroblast markers, NFkB and MYC upregulation, and pro-tumorigenic paracrine secretion. Complementary to this, our published studies show that high intake of dietary AGE after BCa diagnosis increases risk of mortality in postmenopausal women. Conclusions These data demonstrate, for the first time, the oncogenic potential of dietary-AGEs in promoting neoplastic growth. This lays the foundation for strategic changes aimed at reducing cancer incidence and mortality as pharmacological, educational and/or interventional strategies aimed at reducing the dietary-AGE accumulation pool may one day be viewed as universal cancer preventative and/or therapeutic initiatives especially when combined with existing therapies. Funding Sources David P. Turner was supported by grants from the NIH/NCI, R21 CA194469 and U54 CA21096..

scholarly journals Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells

2011 ◽  
Vol 300 (4) ◽  
pp. L516-L525 ◽  
Author(s):  
Naoko Yamakawa ◽  
Tokujiro Uchida ◽  
Michael A. Matthay ◽  
Koshi Makita
Keyword(s):  
Epithelial Cells ◽  
Advanced Glycation End Products ◽  
Alveolar Epithelial Cells ◽  
Advanced Glycation ◽  
Alveolar Epithelial ◽  
Lps Challenge ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products

Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 μg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.

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