Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells

Jeong, So Ra; Park, Ho-Young; Kim, Yoon‐Sook; Lee, Kwang Won

doi:10.1007/s10068-019-00704-7

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…However, other phlorotannins, such as 8,8-bieckol and eckol only partially suppressed MAPK [ 43 ]. Activation of the MAPK pathway stimulated MMP-2 and MMP-9 expression but blocking of ERK and JNK signaling via their inhibitors (PD98059 and SP600125) effectively lowered elevated MMP expressions in kidney proximal epithelial cells [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

Ecklonia cava Extract Exerts Anti-Inflammatory Effect in Human Gingival Fibroblasts and Chronic Periodontitis Animal Model by Suppression of Pro-Inflammatory Cytokines and Chemokines

Jung

Kim

Baek

et al. 2021

Foods

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Periodontitis is one of the most common chronic inflammatory diseases. The anti-inflammatory effect of the extract from brown algae Ecklonia cava was analyzed in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGF-1), the most abundant cells in gingival tissue. The gene expressions of cyclooxygenase-2 and interleukin-6 were decreased by 78 and 50%, respectively, at 100 μg/mL Ecklonia cava extract (ECE) treatment. The gene expressions of matrix metalloproteases (MMP-2 and MMP-8) and chemokines (macrophage inflammatory protein 1-alpha and stromal cell-derived factor 1) were also significantly down-regulated by ECE treatment (p < 0.05). The increased reactive oxygen species (ROS) production in HGF-1 cells by LPS stimulation was decreased by 30% at 100 μg/mL ECE treatment. The mitogen-activated protein kinase pathway and the nuclear factor-kappa B (NF-κB) signal activated by ROS were suppressed by ECE in a dose-dependent manner. ECE treatment (400 mg/kg, 8 weeks) significantly improved alveolar bone resorption in the ligature-induced chronic periodontitis rat model. ECE supplementation also lowered elevated mRNA expression of the receptor activator of nuclear factor-kappa B (RANKL)/osteoprotegerin (OPG) in the gingival tissue (p < 0.05). Therefore, ECE mitigated gingival tissue destruction and bone resorption associated with chronic periodontitis condition.

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Section: Resultsmentioning

confidence: 99%

Ecklonia cava Extract Exerts Anti-Inflammatory Effect in Human Gingival Fibroblasts and Chronic Periodontitis Animal Model by Suppression of Pro-Inflammatory Cytokines and Chemokines

Jung

Kim

Baek

et al. 2021

Foods

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“…RAGE–AGE4 axis-induced apoptosis is correlated with the induction of ER stress markers, such as CHOP, ATF4, and GRP78, via JNK pathway. In the previous study, AGE4 treatment induced RAGE-dependent cell inflammation in rat kidney epithelial cells (NRK-52E) through the ERK, JNK, and NF-κB pathways [ 12 ]. JNK and NF-κB are the main oncogenic signaling pathways linked to ER stress, which leads to nonalcoholic steatohepatitis and hepatocellular carcinoma [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…After 24 h, total mRNA and protein were extracted to examine the RAGE knockdown level. The primer sequence was mentioned in a previous study [ 12 ], and the knockdown efficiency of mRNA and protein was determined based on a comparison with negative control siRNA.…”

Section: Methodsmentioning

confidence: 99%

“…Methylglyoxal (MGO), a major electrophilic dicarbonyl compound, is generated as a nonenzymatic breakdown product of a triosephosphate intermediate in the glycolytic process and has been linked to dicarbonyl stress, which leads to the development of AGEs and related cellular dysfunction [ 10 , 11 ]. We previously showed that the treatment of NRK-52E kidney cells with MGO-derived AGEs (AGE4) leads to an increase in the protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 via AGE4–RAGE interactions [ 12 ]. Endoplasmic reticulum (ER) stress is an important mechanism that induces diabetes [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells

Jeong

Lee

2021

IJMS

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Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.

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“…Preparation of AGE‐BSA was performed according to a previous method (Jeong, Park, Kim, & Lee, 2020). BSA (20 mg/mL) was incubated with 100 µM methylglyoxal and 0.02% sodium azide in 100 mM phosphate buffer (pH 7.4) for 7 days at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory effect of caffeic acid on advanced glycation end product‐induced renal fibrosis in vitro: A potential therapeutic target

Jeon

Nam

Lee

2021

Journal of Food Science

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Advanced glycation end products (AGEs) are formed from amino acids and reducing sugars through nonenzymatic Maillard reaction. AGEs are known to induce oxidative stress, which may cause fibrosis or cancer. In this study, we investigated the protective effect of caffeic acid (CA) on AGE‐mediated kidney epithelial to mesenchymal transition (EMT) in human HK‐2 cells. Exposure to 100 µg/mL of AGEs by kidney epithelial cells raised the production of reactive oxygen species by 5.2‐fold and decreased levels of glutathione. In addition, cardamonin, a β‐catenin inhibitor, was used to determine the signaling pathway for β‐catenin in which cardamonin inhibited the AGEs‐induced translocation of β‐catenin into the nucleus, resulting in an inhibition of the EMT process. Similarly, our findings showed that, close to the control level, CA treatment decreased AGE‐mediated oxidative stress, loss of E‐cadherin expression, and overexpression of α‐smooth muscle actin and fibronectin by inactivation of the β‐catenin pathway. Furthermore, AGE treatment enhanced the expression of collagen type I (1.99‐fold) as well as the activity of metalloproteinases 2 (1.86‐fold) and 9 (2.79‐fold), but such increase was inhibited by the pretreatment of CA. In conclusion, this study determined the inhibitory effect of CA on AGE‐induced β‐catenin signaling, which prevented the occurrence of EMT in kidney epithelial cells. This suggests that CA may be a potential target for AGE‐induced renal fibrosis.Practical ApplicationExposure of kidney epithelial cells to advanced glycation end products (AGEs) leads to a rise in reactive oxygen species and a decrease in glutathione, thereby increasing oxidative stress that may cause fibrosis. However, treatment of kidney cells with caffeic acid (CA) prior to their exposure to AGEs lowers oxidative stress and decreases fibrosis. This research reveals the beneficial influence of CA on renal fibrosis in laboratory‐cultured kidney cells (in vitro), which makes CA a potential therapeutic target for AGE‐induced fibrosis.

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Methylglyoxal-derived advanced glycation end products induce matrix metalloproteinases through activation of ERK/JNK/NF-κB pathway in kidney proximal epithelial cells

Cited by 15 publications

References 33 publications

Ecklonia cava Extract Exerts Anti-Inflammatory Effect in Human Gingival Fibroblasts and Chronic Periodontitis Animal Model by Suppression of Pro-Inflammatory Cytokines and Chemokines

Ecklonia cava Extract Exerts Anti-Inflammatory Effect in Human Gingival Fibroblasts and Chronic Periodontitis Animal Model by Suppression of Pro-Inflammatory Cytokines and Chemokines

Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells

Inhibitory effect of caffeic acid on advanced glycation end product‐induced renal fibrosis in vitro: A potential therapeutic target

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