Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in  Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Lu, Yu; Zhao, Yanbo; Xu, Shengjie; Ding, Fang; Jin, Chongying; Fu, Guosheng; Weng, Shaoxiang

doi:10.3390/ijms14022242

Cited by 28 publications

(18 citation statements)

References 48 publications

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“…We found that the RAGE levels were unaffected by AGEs in BME, in contrast to others who have observed the upregulation of RAGE levels by AGEs [44,50]. However, most of these studies used exogenous AGE preparations dissimilar to the BME-bound AGEs in our study.…”

Section: Discussioncontrasting

confidence: 93%

AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells

Raghavan

Nagaraj

2016

Glycoconj J

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Basement membrane (BM) proteins accumulate chemical modifications with age. One such modification is glycation, which results in the formation of advanced glycation endproducts (AGEs). In a previous study, we reported that AGEs in the human lens capsule (BM) promote the TGFβ2-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells, which we proposed as a mechanism for posterior capsule opacification (PCO) or secondary cataract formation. In this study, we investigated the role of a receptor for AGEs (RAGE) in the TGFβ2-mediated EMT in a human lens epithelial cell line (FHL124). RAGE was present in FHL124 cells, and its levels were unaltered in cells cultured on either native or AGE-modified BM or upon treatment with TGFβ2. RAGE overexpression significantly enhanced the TGFβ2-mediated EMT responses in cells cultured on AGE-modified BM compared with the unmodified matrix. In contrast, treatment of cells with a RAGE antibody or EN-RAGE (an endogenous ligand for RAGE) resulted in a significant reduction in the TGFβ2-mediated EMT response. This was accompanied by a reduction in TGFβ2-mediated Smad signaling and ROS generation. These results imply that the interaction of matrix AGEs with RAGE plays a role in the TGFβ2-mediated EMT of lens epithelial cells and suggest that the blockade of RAGE could be a strategy to prevent PCO and other age-associated fibrosis.

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Section: Discussioncontrasting

confidence: 93%

AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells

Raghavan

Nagaraj

2016

Glycoconj J

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“…Classical PKCs (including the α, β1, β2, and γ isoforms) are calcium-dependent, novel PKCs (including the δ, ε, η, and θ isoforms), and atypical PKCs (including the ξ, λ, and τ isoforms) are calcium independent. Several studies have shown that the PKC family, mainly classical PKCs, are implicated in Cx43 phosphorylation at multiple serines (S365, S368, S369, S372, and S373) [36,37], expression [38] and GJIC regulation [39][40][41]. We found, for the first time, that inhibition of PKC pathways by GF109203X could also block MC proliferation ( Fig.…”

Section: Effects Of Aldo On the Intracellular Calcium Concentrationsmentioning

confidence: 49%

Beyond Gap Junction Channel Function: the Expression of Cx43 Contributes to Aldosterone-Induced Mesangial Cell Proliferation via the ERK1/2 and PKC Pathways

Zhang

Han

Wang³

et al. 2015

Cell Physiol Biochem

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Aims: This study aimed to explore the precise mechanism and signaling pathways of mesangial cell (MC) proliferation from a new point of view considering Connexin 43 (Cx43). Methods: MC proliferation was measured by the incorporation of 3H-thymidine (3H-TdR). Cx43 was over-expressed in MC cells using lipofectamine 2000, and the expression level was tested with reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. The gap junction channel function was explored by Lucifer Yellow scrape loading and dye transfer (SLDT), and the intracellular calcium concentrations ([Ca²⁺]_i) were characterized by confocal microscopy on cells loaded with Fura-3/AM. Results: There was an inverse correlation between Cx43 expression and MC proliferation (P<0.05). SLDT studies revealed that there was no difference in the gap junction channel function between the normal and Aldosterone (Aldo)-stimulated groups (P>0.05). Our data also showed that the mineralcorticoid receptor (MR) antagonist spironolactone, ERK1/2 inhibitor PD98059 and PKC inhibitor GF109203X could attenuate the down-regulation of Cx43 expression in Aldo-induced MC proliferation; however, the PI3K inhibitor LY294002 could block MC proliferation without affecting Cx43 expression at either the mRNA or protein level. In addition, Aldo promoted MC proliferation in parallel with increasing [Ca²⁺]_i (P<0.05), suggesting that the classical PKC pathway might be activated. Conclusions: Our study provides preliminary evidence that Cx43 is an important regulator of Aldo-promoted MC proliferation. Furthermore, reduced Cx43 expression promoted MC proliferation independent of the gap junction channel function, and this process might be mediated through the ERK1/2- and PKC-dependent pathways.

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“…This may explain the non-significant changes in RAGE expression on tissues studied because the RAGE protein could be expressed in other isoforms such as sRAGE. In addition to that, AGE-mediated up-regulation of RAGE expression is dependent on the exposure duration and concentration of AGE [48]. Since there was no significant difference in AGE level among the groups in the present study, AGEmediated increase in RAGE expression was not significant as well.…”

Section: Rage Gene In Rats Undergoes Various Alternative Splicing Andcontrasting

confidence: 47%

Low-dose Insulin Treatment Ameliorate Glucose Metabolism in Type 1 Diabetic Rats

Ng¹,

Ton²

2015

J Diabetes Metab

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Study background: Type 1 diabetes is an insulin-dependent diabetes mellitus (IDDM) because the body does not produce sufficient insulin for daily need. Persistent high glucose level in the blood circulation can stimulate the advanced glycation end products/receptor for AGEs (AGE/RAGE) pathway leading to diabetic complications. Currently, there is no preventive measure for IDMM with only treatment focusing on delaying the onset of diabetic complications. This study aimed to investigate how the different insulin regimens given affect the glycemic control and glucose metabolism in type 1 diabetes. The effects on the AGE/RAGE axis were determined as well.Methods: Twenty-one male Sprague-Dawley rats were randomly assigned into three groups (Group A: streptozotocin-induced diabetic rats given high-dose insulin [5-7U per day], Group B: streptozotocin-induced diabetic rats given low-dose insulin [0-3U per day], Group C: non-diabetic control). Throughout the eight-week treatment, the body weight, systolic blood pressure and non-fasting blood glucose concentration were monitored. After eight weeks of treatment, fasting blood glucose concentration, glycated haemoglobin (HbA1c), nuclear factor kappa B (NF-κB), AGE level and RAGE expression were measured.Results: High-dose insulin treatment impaired glucose metabolism. On the contrary, diabetic rats receiving lowdose insulin showed reduced glucose level and improved insulin sensitivity towards the end of experiment. HbA1c level was significantly lower in low-dose insulin treated rats while NF-κB level was significantly lower in high-dose insulin treated rats (p ≤ 0.05). There was no significant difference in AGE levels in all the groups (p>0.05) and only the heart tissues from the low-dose insulin treated group showed significant down regulation of the RAGE gene expression (p ≤ 0.05).

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Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Cited by 28 publications

References 48 publications

AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells

AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells

Beyond Gap Junction Channel Function: the Expression of Cx43 Contributes to Aldosterone-Induced Mesangial Cell Proliferation via the ERK1/2 and PKC Pathways

Low-dose Insulin Treatment Ameliorate Glucose Metabolism in Type 1 Diabetic Rats

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