scholarly journals High glucose promotes TGF-β1 production by inducing FOS expression in human peritoneal mesothelial cells

2015 ◽  
Vol 20 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Keiko Kokoroishi ◽  
Ayumu Nakashima ◽  
Shigehiro Doi ◽  
Toshinori Ueno ◽  
Toshiki Doi ◽  
...  
Keyword(s):  
High Glucose ◽  
Mesothelial Cells ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
Fos Expression ◽  
Tgf Β1

scholarly journals Activation of General Control Nonderepressible-2 Kinase Ameliorates Glucotoxicity in Human Peritoneal Mesothelial Cells, Preserves Their Integrity, and Prevents Mesothelial to Mesenchymal Transition

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 832
Author(s):  
Theodoros Eleftheriadis ◽  
Georgios Pissas ◽  
Georgia Antoniadi ◽  
Evdokia Nikolaou ◽  
Spyridon Golfinopoulos ◽  
...  
Keyword(s):  
High Glucose ◽  
Cell Apoptosis ◽  
Glucose Transporter ◽  
Mesothelial Cells ◽  
General Control ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Ultrafiltration Failure ◽  
Human Peritoneal Mesothelial Cells ◽  
Tgf Β1

Along with infections, ultrafiltration failure due to the toxicity of glucose-containing peritoneal dialysis (PD) solutions is the Achilles’ heel of PD method. Triggered by the protective effect of general control nonderepressible-2 (GCN-2) kinase activation against high-glucose conditions in other cell types, we evaluated whether the same occurs in human peritoneal mesothelial cells. We activated GCN-2 kinase with halofuginone or tryptophanol, and assessed the impact of this intervention on glucose transporter-1, glucose transporter-3, and sodium-glucose cotransporter-1, glucose influx, reactive oxygen species (ROS), and the events that result in glucotoxicity. These involve the inhibition of glyceraldehyde 3-phosphate dehydrogenase and the diversion of upstream glycolytic products to the aldose pathway (assessed by D-sorbitol), the lipid synthesis pathway (assessed by protein kinase C activity), the hexosamine pathway (determined by O-linked β-N-acetyl glucosamine-modified proteins), and the advanced glycation end products generation pathway (assessed by methylglyoxal). Then, we examined the production of the profibrotic transforming growth factor-β1 (TGF-β1), the pro-inflammatory interleukin-8 (IL-8). Cell apoptosis was assessed by cleaved caspase-3, and mesothelial to mesenchymal transition (MMT) was evaluated by α-smooth muscle actin protein. High-glucose conditions increased glucose transporters, glucose influx, ROS, all the high-glucose-induced harmful pathways, TGF-β1 and IL-8, cell apoptosis, and MMT. Halofuginone and tryptophanol inhibited all of the above high glucose-induced alterations, indicating that activation of GCN-2 kinase ameliorates glucotoxicity in human peritoneal mesothelial cells, preserves their integrity, and prevents MMT. Whether such a strategy could be applied in the clinic to avoid ultrafiltration failure in PD patients remains to be investigated.

Possible Role of Hepatocyte Growth Factor in Regeneration of Human Peritoneal Mesothelial Cells

2005 ◽  
Vol 28 (2) ◽  
pp. 141-149 ◽  
Author(s):  
Y. Naiki ◽  
K. Matsuo ◽  
T. Matsuoka ◽  
Y. Maeda
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
High Glucose ◽  
Glucose Solution ◽  
Mesothelial Cells ◽  
Matrix Metalloproteinase 2 ◽  
High Concentration ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
Hepatocyte Growth

Human peritoneal mesothelial cells (HPMCs) play an important role in peritoneal functions. During long term peritoneal dialysis, it has been reported that HPMCs are damaged by high glucose solution via the signal of transforming growth factor (TGF)- ß1 produced by HPMCs. In this study, we focused on the effect of hepatocyte growth factor (HGF), known as an anti-fibrotic and anti-TGF-ß1 agent, on HPMCs damaged by high glucose solution. HPMCs were isolated from specimens of the omentum from nonuremic patients after informed consent had been obtained. After confirming adhesion for 6 hours, 100 μL of DMEM with 0.5%FCS were added at different concentrations (D-glucose; 6, 30mM) with or without HGF (10, 30, 100 ng/mL) for 48 hours. We examined the effects of a high concentration of glucose and then focused on following four critical points: 1) the production of HGF from HPMCs exposed to a high concentration of glucose, 2) the expression of c-Met on HPMCs, 3) the viability of those cells, and 4) matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinase-2 (TIMP-2). The following significant changes are described herein: high glucose solution and TGF-ß1 i) decreased HGF production from HPMCs and ii) up-regulated expression of c-Met on HPMCs, and addition of HGF iii) restored viability of HPMCs damaged by glucose, iv) suppressed TGF-ß1 production by HGF, and v) induced up-regulation of MMP-2 and decreased TIMP-2 production by HPMCs. Levels of HGF decreased by high concentrations of glucose in the peritoneal cavity may induce the loss of HPMCs and thereby result in peritoneal fibrosis. These results suggest that HGF is an effective agent in the regeneration of peritoneal membrane damaged by high glucose solution.

EndothelinB Receptor Blocker Inhibits High Glucose-Induced Synthesis of Fibronectin in Human Peritoneal Mesothelial Cells

2006 ◽  
Vol 26 (3) ◽  
pp. 393-401 ◽  
Author(s):  
Miyuki Shimizu ◽  
Yoshitaka Ishibashi ◽  
Fumika Taki ◽  
Hideki Shimizu ◽  
Ichiro Hirahara ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Mrna Expression ◽  
Real Time ◽  
High Glucose ◽  
Mesothelial Cells ◽  
Peritoneal Fibrosis ◽  
Peritoneal Mesothelial Cells ◽  
Protein Levels ◽  
Human Peritoneal Mesothelial Cells

Background Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC). Methods HPMC were cultured with 4% d- or l-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry. Results d-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated HPMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1. Conclusion The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be useful in preventing FN production in HPMC.

scholarly journals Diltiazem suppresses collagen synthesis and IL-1β-induced TGF-β1 production on human peritoneal mesothelial cells

2006 ◽  
Vol 21 (5) ◽  
pp. 1340-1347 ◽  
Author(s):  
Cheng-Chung Fang ◽  
Chung-Jen Yen ◽  
Yung-Ming Chen ◽  
Tzong-Shinn Chu ◽  
Ming-Tsan Lin ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Mesothelial Cells ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
Tgf Β1

TGF-β1 Induced by High Glucose is Controlled by Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker on Cultured Human Peritoneal Mesothelial Cells

2005 ◽  
Vol 25 (5) ◽  
pp. 483-491 ◽  
Author(s):  
Yasufumi Kyuden ◽  
Takafumi Ito ◽  
Takao Masaki ◽  
Noriaki Yorioka ◽  
Nobuoki Kohno
Keyword(s):  
Angiotensin Converting Enzyme ◽  
High Glucose ◽  
Enzyme Inhibitor ◽  
Converting Enzyme ◽  
Rt Pcr ◽  
Peritoneal Fibrosis ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
Peritoneal Function ◽  
Tgf Β1

Background Loss of peritoneal function is a major complication associated with long-term peritoneal dialysis. Observed changes include loss and degeneration of the mesothelium, submesothelial thickening, alterations in the structure and number of blood vessels, and reduplication of the vascular basement membrane. Exposure to high glucose concentrations in peritoneal dialysis solutions is known to cause injury to cultured human peritoneal mesothelial cells (HPMC) as a result of overexpression of transforming growth factor beta 1 (TGF-β1). Previous studies have demonstrated that angiotensin II (AII) increases expression of TGF-β1 in a number of different cell types; although this has not been demonstrated in HPMC. Objective To clarify possible mechanisms involved in peritoneal fibrosis, we investigated whether HPMC expressed AII-forming pathway mRNA and whether increases in AII induced by high glucose contribute to the production of TGF-β1. We also examined the effects of the angiotensin-converting enzyme inhibitor (ACEI) perindoprilat and the AII receptor blocker (ARB) candesartan on expression of TGF-β1 and proliferation of HPMC. Methods Expression of mRNA for the AII-forming pathway and TGF-β1 in HPMC was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative RT-PCR. Levels of AII and TGF-β1 following 48 hours of incubation of the cells in a range of glucose concentrations were measured by enzyme immunoassay and enzyme linked immunosorbent assay respectively. The effect of glucose on cell proliferation was examined using the water-soluble tetrazolium salt WST-1 and [3H]-thymidine uptake. We also investigated the effect of ACEI and ARB on the expression of TGF-β1 and the proliferation of HPMC incubated at high glucose for 48 hours. Results AII-forming pathway mRNA was detected in HPMC, with expression of angiotensinogen, angiotensin-converting enzyme (ACE), AII type 1 receptor, and TGF-β1 mRNA increasing following exposure to glucose according to glucose concentration. High glucose was also shown to increase the production of AII and TGF-β1 and decrease the proliferation of HPMC. In contrast, we found that both the ACEI and the ARB attenuated the increase in TGF-β1 production and reduced cell proliferation caused by exposure to high glucose. These effects were greater with a combination of the two drugs. Conclusion The present study provides evidence that ( 1 ) HPMC express mRNA for the AII-forming pathway; ( 2 ) ACEI and ARB inhibit the TGF-β1 production induced by high glucose; ( 3 ) the AII-forming pathway is one mechanism by which high glucose causes production of TGF-β1. In addition to having antihypertensive and renal-protective effects, combination therapy with an ACEI and an ARB may also be effective in preventing loss of peritoneal function and decreasing peritoneal fibrosis.

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