Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)

Oldfield, Matthew D; Bach, Leon A.; Forbes, Josephine M.; Nikolic‐Paterson, David J.; McRobert, Anne; Thallas, Vicki; Atkins, Robert C.; Osicka, Tanya M; Jerums, George; Cooper, Mark E.

doi:10.1172/jci11951

Cited by 393 publications

(231 citation statements)

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“…AGEs could interact with RAGE, a receptor of AGEs, and enhance the TGFβ2 response. The interaction between RAGE and AGEs has been implicated in fibrosis in other tissues (Oldfield et al ., 2001; Song et al ., 2011). Another possibility is that AGEs in the capsule could affect integrins, which are major conduits between epithelial cells and the lens capsule and promote the TGFβ2‐mediated EMT response.…”

Section: Discussionmentioning

confidence: 99%

“…Glycation is the reaction of carbonyl compounds, including glucose, ascorbate oxidation products, and methylglyoxal, that forms a variety of structurally diverse stable adducts in proteins; these adducts are collectively known as advanced glycation endproducts or AGEs (Singh et al ., 2001). Several studies have shown the accumulation of AGEs in the aged BM of the kidneys, lungs, and lens capsule (Bailey et al ., 1993; Oldfield et al ., 2001; Song et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

“…Several studies have suggested a role for AGEs in EMT; kidney tubular epithelial cell EMT and fibrosis, which occur in diabetic nephropathy, are mediated through engagement of the receptor for AGEs (RAGE) with AGEs, followed by the synthesis of connective tissue growth factor and can be inhibited by AGE inhibitors (Oldfield et al ., 2001; Burns et al ., 2006; Sugimoto et al ., 2007). The AGE–RAGE interaction also enhances TGFβ1 expression and induces fibrosis of the peritoneal membrane (De Vriese et al ., 2003).…”

Section: Introductionmentioning

confidence: 99%

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AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

et al. 2016

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SummaryProteins in basement membrane (BM) are long‐lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial‐to‐mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age‐dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC‐MS/MS. The TGFβ2‐mediated upregulation of the mRNA levels (by qPCR) of EMT‐associated proteins was significantly enhanced in cells cultured on AGE‐modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2‐mediated α‐smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2‐mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes‐associated fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

et al. 2016

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“…The EMT defines a phenotypic conversion of primary epithelial cells into mesenchymal cells, characterized by loss of epithelial cells makers such as E-cadherin, ZO-1 and gain of mesenchymal cells makers such as vimentin and fibronectin [6]. Tubular EMT can be induced by TGF-β1 [7,8,9,10,11,12], advanced-glycation end products [13,14], and angiotensin II [15], but TGF-β1 is probably a major inducer of EMT, because TGF-β1 signaling is sufficient to induce EMT in epithelial cells [9,11]. Whereas TGF-β1 responses are initiated by the interaction of TGF-β1 with cell surface receptors [16], the intracellular signaling pathway involved in EMT are complex.…”

Section: Introductionmentioning

confidence: 99%

Akt2 Mediates TGF-�1-Induced Epithelial to Mesenchymal Transition by Deactivating GSK3�/Snail Signaling Pathway in Renal Tubular Epithelial Cells

Lan

Qi²,

Du³

2014

Cell Physiol Biochem

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Background: The epithelial-mesenchymal transition (EMT) induced by growth factors or cytokines, particularly transforming growth factor-β (TGF-β1), plays an important role in kidney tubulointerstitial injury. However, signaling pathways mediating TGF-β1-induced EMT are not precisely known. In this study, we examined the role of Akt2 on EMT. Methods: HK-2 cells were exposed to 10 ng/ml TGF-β1 to establish a model of EMT. The expression of proteins were detected by western blot assay and Immunofluorescence. The levels of genes were tested by RT-PCR. Results: We found that treatment of HK-2 cells, a human proximal tubular cell line, with 10 ng/ml TGF-β1 resulted in activation of phosphatidylinositol 3-kinase (PI3K)/Akt2 signaling as evidenced by increased p-PI3K, Akt2 and p-Akt (Ser 473) expression. Importantly, TGF-β1 treatment decreased zona occludins 1 (ZO-1) and E-cadherin (epithelial markers) expression, increased fibronectin and vimentin (mesenchymal makers) expression, which were prevented by Ly294002 (the inhibitor of PI3K) or small interfering RNA (siAkt2), suggesting that Akt2 mediated TGF-β1-induced EMT. Meanwhile, RNA and protein levels of Snail1, the key inducer of EMT, were significantly elevated in TGF-β1-treated HK-2 cells. TGF-β1 also induced inactivation of glycogen synthase kinase-3β (GSK3β), an endogenous inhibitor of Snail. Knockdown of Akt2 using siRNAs or the PI3K inhibitor Ly294002 inhibited TGF-β1-induced phosphorylation of GSK3β and expression of Snail1. Conclusion: These findings revealed that knockdown of Akt2 antagonized TGF-β1-induced EMT by inhibiting GSK3β/Snail signaling pathway.

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“…22 Primer sequences for the analyzed gene of interest are detailed in Table in the online-only Data Supplement.…”

mentioning

confidence: 99%

AT2R Agonist, Compound 21, Is Reno-Protective Against Type 1 Diabetic Nephropathy

et al. 2015

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Abstract-The hemodynamic and nonhemodynamic effects of angiotensin II on diabetic complications are considered to be primarily mediated by the angiotensin II type 1 receptor subtype. However, its biological and functional effect mediated through the angiotensin II type 2 receptor subtype is still unclear. Activation of the angiotensin II type 2 receptors has been postulated to oppose angiotensin II type 1 receptor-mediated actions and thus attenuate fibrosis. This study aimed to elucidate the reno-protective role of the novel selective angiotensin II type 2 receptor agonist, Compound 21, in an experimental model of type 1 diabetic nephropathy. Compound 21 treatment significantly attenuated diabetes mellitus-induced elevated levels of cystatin C, albuminuria, mesangial expansion, and glomerulosclerosis in diabetic mice. Moreover, Compound 21 markedly inhibited the expression of various proteins implicated in oxidative stress, inflammation, and fibrosis, in association with decreased extracellular matrix production. These findings demonstrate that monotherapy of Compound 21 is protective against the progression of experimental diabetic nephropathy by inhibiting renal oxidative stress, inflammation, and fibrosis. Materials and MethodsRefer to Materials and Methods in the online-only Data Supplement for greater details. In Vivo Experimental ProcedureSix-week-old ApoE −/− mice were rendered diabetic via 5-daily intraperitoneal injection of streptozotocin at 55 mg/kg/d (Sigma-Aldrich, St Louise, MO). Diabetic animals were subjected to either a vehicle (0.1 mol/L citrate buffer) or C21 (1 mg/kg/d; Vicore Pharma AB, Göteborg, Sweden) treatment via daily gavaging, over a 20-week period. Additional subgroups of nondiabetic mice subjected to similar treatments were also studied concurrently. In Vitro Experimental ProcedureMouse mesangial cells cultured in normal (5 mmol/L) and high (25 mmol/L) glucose conditions were treated with C21 (0.1-1 μmol/L) in the absence or presence of Ang II (3 μmol/L; Sigma-Aldrich) for 72 hours. RNA and proteins were then extracted from cell layers using Trizol reagent (Life Technologies, Rockville, MD) according to the manufacturer's instructions. Metabolic and Renal Functional MeasurementsAssessment of body weight, metabolic parameters, and blood pressure were performed as described. 19 Collected serum and urine samples were assayed for cystatin C and albuminuria level, respectively, by a kit-based enzyme-linked immunosorbent assay (ELISA). Glomerulosclerotic Injury AssessmentParaffin-embedded kidney sections were subjected to periodic acid-schiff staining for glomerulosclerotic injury assessment, as described. 20 Nuclei free area of periodic acid-schiff-positively stained glomeruli were expressed as a percentage of total glomerular area for quantification of mesangial area. 21Quantitative Real-time PCR Gene expression was analyzed by quantitative real-time PCR (qRT-PCR) using the Taqman System on an ABI Prism 7500 Sequence Detector (Applied Biosystems, Foster City, CA) as described. 22Prim...

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Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE)

Cited by 393 publications

References 53 publications

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

Akt2 Mediates TGF-�1-Induced Epithelial to Mesenchymal Transition by Deactivating GSK3�/Snail Signaling Pathway in Renal Tubular Epithelial Cells

AT2R Agonist, Compound 21, Is Reno-Protective Against Type 1 Diabetic Nephropathy

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