Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome

Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated.Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR.Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2.Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.

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Effects of Danggui Buxue Tang, a traditional Chinese herbal decoction, on high glucose-induced proliferation and expression of extracellular matrix proteins in glomerular mesangial cells

Natural Product Research ◽

10.1080/14786419.2010.546796 ◽

2012 ◽

Vol 26 (11) ◽

pp. 1022-1026 ◽

Cited By ~ 13

Author(s):

Hao-Liang Ke ◽

Ying-Wen Zhang ◽

Bi-Fa Zhou ◽

Rui-Tang Zhen

Keyword(s):

Extracellular Matrix ◽

High Glucose ◽

Mesangial Cells ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Glomerular Mesangial Cells ◽

Danggui Buxue Tang ◽

Chinese Herbal ◽

Herbal Decoction

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SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate

Biomolecules ◽

10.3390/biom10111573 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1573

Author(s):

Michael S. Balzer ◽

Song Rong ◽

Johannes Nordlohne ◽

Jan D. Zemtsovski ◽

Sonja Schmidt ◽

...

Keyword(s):

High Glucose ◽

Structural Changes ◽

Glucose Transporter ◽

Transforming Growth Factor ◽

Sglt2 Inhibitor ◽

Mesothelial Cells ◽

Peritoneal Fibrosis ◽

Peritoneal Mesothelial Cells ◽

Ultrafiltration Failure

Peritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis, and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study, wildtype C57Bl/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity, and peritoneal equilibration testing (PET) status for glucose, urea, and creatinine were analyzed. Expression of SGLT and facilitative glucose transporters (GLUT) was analyzed by real-time PCR, immunofluorescence, and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent transforming growth factor (TGF-β) concentrations, peritoneal thickening, and fibrosis, as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high-glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high-glucose conditions in human and murine peritoneal mesothelial cells. Proinflammatory cytokine release in macrophages was reduced only when cultured in high-glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high-glucose PD.

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High Glucose Increases Binding of Lysyl Oxidase to Extracellular Matrix Proteins: Implications for Diabetic Retinopathy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.61.4.40 ◽

2020 ◽

Vol 61 (4) ◽

pp. 40 ◽

Cited By ~ 2

Author(s):

Ngan-Ha Nguyen ◽

Dongjoon Kim ◽

Sayon Roy

Keyword(s):

Extracellular Matrix ◽

Diabetic Retinopathy ◽

High Glucose ◽

Lysyl Oxidase ◽

Extracellular Matrix Proteins ◽

Matrix Proteins

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SGLT2 inhibition by intraperitoneal dapagliflozin mitigates peritoneal fibrosis and ultrafiltration failure in a mouse model of chronic peritoneal exposure to high-glucose dialysate

10.1101/2020.11.04.366724 ◽

2020 ◽

Author(s):

Michael S. Balzer ◽

Song Rong ◽

Johannes Nordlohne ◽

Jan D. Zemtsovski ◽

Sonja Schmidt ◽

...

Keyword(s):

High Glucose ◽

Structural Changes ◽

Glucose Transporter ◽

Sglt2 Inhibitor ◽

Mesothelial Cells ◽

Peritoneal Fibrosis ◽

Monocyte Chemoattractant Protein 1 ◽

Peritoneal Mesothelial Cells ◽

Ultrafiltration Failure

ABSTRACTPeritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study wildtype C57Bl/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity and PET status for glucose, urea and creatinine were analyzed. Expression of SGLT and GLUT was analyzed by real-time PCR, immunofluorescence and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent TGF-β concentrations, peritoneal thickening and fibrosis as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high glucose conditions in human and murine peritoneal mesothelial cells. Pro-inflammatory cytokine release in macrophages was reduced only when cultured in high glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high glucose PD.

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Chromosomal Expression of the Haemophilus influenzae Hap Autotransporter Allows Fine-Tuned Regulation of Adhesive Potential via Inhibition of Intermolecular Autoproteolysis

Journal of Bacteriology ◽

10.1128/jb.185.5.1608-1615.2003 ◽

2003 ◽

Vol 185 (5) ◽

pp. 1608-1615 ◽

Cited By ~ 27

Author(s):

Doran L. Fink ◽

Joseph W. St. Geme

Keyword(s):

Extracellular Matrix ◽

Epithelial Cells ◽

Haemophilus Influenzae ◽

Critical Role ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Passenger Domain ◽

Respiratory Epithelial Cells ◽

Bacterial Aggregation ◽

Respiratory Epithelial

ABSTRACT The Haemophilus influenzae Hap autotransporter is a nonpilus adhesin that promotes adherence to respiratory epithelial cells and selected extracellular matrix proteins and facilitates bacterial aggregation and microcolony formation. Hap consists of a 45-kDa outer membrane translocator domain called Hapβ and a 110-kDa extracellular passenger domain called HapS. All adhesive activity resides within HapS, which also contains protease activity and directs its own secretion from the bacterial cell surface via intermolecular autoproteolysis. In the present study, we sought to determine the relationship between the magnitude of Hap expression, the efficiency of Hap autoproteolysis, and the level of Hap-mediated adherence and aggregation. We found that a minimum threshold of Hap precursor was required for autoproteolysis and that this threshold approximated expression of Hap from a chromosomal allele, as occurs in H. influenzae clinical isolates. Chromosomal expression of wild-type Hap was sufficient to promote significant adherence to epithelial cells and extracellular matrix proteins, and adherence was enhanced substantially by inhibition of autoproteolysis. In contrast, chromosomal expression of Hap was sufficient to promote bacterial aggregation only when autoproteolysis was inhibited, indicating that the threshold for Hap-mediated aggregation is above the threshold for autoproteolysis. These results highlight the critical role of autoproteolysis and an intermolecular mechanism of cleavage in controlling the diverse adhesive activities of Hap.

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