Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through β-catenin signaling

Padwal, Manreet; Siddique, Imad; Wu, Li; Tang, Katelynn; Boivin, Félix; Liu, Limin; Robertson, John C.; Bridgewater, Darren; West‐Mays, Judith A.; Gangji, Azim S.; Brimble, K. Scott; Margetts, Peter J.

doi:10.1093/ndt/gfw076

Cited by 17 publications

(26 citation statements)

References 53 publications

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“…It is well known that the disruption of adherent junctions is an early step and one of the key events in MMT23. In this context, it has been reported that MMT and peritoneal membrane injury are mediated through cleavage of E-cadherin by MMP-9 and induction of β-catenin signaling32. Interestingly, we observed that the Wnt/β-catenin pathway was deregulated in both E and NE cells (Fig.…”

Section: Resultssupporting

confidence: 52%

“…Interestingly, peritoneal transport of the PD patients from whom the cells were harvested was associated with the ex vivo expression levels of molecules that were over-expressed during MMT in cultured effluent MC2427. As a proof of concept, levels of MMT-associated molecules in the PD effluent, including VEGF, CTGF/CCN2, Gremlin-1 (GREM1), and MMP9 were found to correlate with the peritoneal transport status2829303132. Herein, by using whole genome microarray analysis of MCs undergoing MMT in vitro and ex vivo , we aimed to identify novel molecular biomarkers that may facilitate diagnosis of the integrity and functionality of the patient’s peritoneum and hence allow early adaption of treatment to the patient’s needs.…”

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confidence: 98%

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Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Ruiz-Carpio

Sandoval

Aguilera

et al. 2017

Sci Rep

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Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD.

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Section: Resultssupporting

confidence: 52%

mentioning

confidence: 98%

Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Ruiz-Carpio

Sandoval

Aguilera

et al. 2017

Sci Rep

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“…Angiogenesis is one of the pathologic consequences following long-term PD [ 4 ]. Previous studies suggested that VEGF expression is also implicated in peritoneal fibrosis [ 4 , 41 ]. To investigate whether HDAC6 inhibition is involved in angiogenesis, we examined the expression level of CD31 (a marker of endothelial cells) and VEGF by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Liu

et al. 2017

Oncotarget

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The role of histone deacetylase 6 (HDAC6) in peritoneal fibrosis remains unknown. In this study, we examined the effect of HDAC6 inhibition on the epithelial–mesenchymal transition (EMT) of peritoneal mesothelial cells and development of peritoneal fibrosis. Treatment with tubastatin A, a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA inhibited transforming growth factor β1-induced EMT, as evidenced by decreased expression of α-smooth muscle actin, collagen I and preserved expression of E-cadherin in cultured human peritoneal mesothelial cells. In a mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of TA prevented thickening of the submesothelial region and decreased expression of collagen I and α-SMA. Mechanistically, tubastatin A treatment inhibited expression of TGF-β1 and phosphorylation of Smad-3, epidermal growth factor receptor, STAT3, and NF-κBp65. HDAC6 inhibition also suppressed production of multiple inflammatory cytokines/chemokines and reduced the infiltration of macrophages to the injured peritoneum. Moreover, tubastatin A was effective in inhibiting peritoneal increase of CD31(+) blood vessels and expression of vascular endothelial growth factor in the injured peritoneum. Collectively, these results suggest that HDAC6 inhibition can attenuate peritoneal fibrosis by inhibiting multiple pro-fibrotic signaling pathways, EMT, inflammation and blood vessel formation.

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“…Degradation of the vascular basement membrane is an indispensable step for the invasion of endothelial cells. An increase in MMPs is associated with tumour invasion, metastasis and angiogenesis (38). Among the proteolytic enzymes, MMP9 has been reported both in vivo and in vitro, to have an important role in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Luteolin inhibits angiogenesis of the M2‑like TAMs via the downregulation of hypoxia inducible factor‑1α and the STAT3 signalling pathway under hypoxia

Fang

Chen

et al. 2018

Mol Med Report

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The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour‑associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2‑like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia‑inducible factor‑1α (HIF‑1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase‑9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF‑1 and phosphorylated‑signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2‑like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF‑1α and STAT3 signalling pathways.

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Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through β-catenin signaling

Abstract: Our data suggest that MMP9 is involved in peritoneal membrane injury possibly through cleavage of E-cadherin and induction of β-catenin signaling. MMP9 is a potential biomarker for peritoneal membrane injury and is a therapeutic target to protect the peritoneal membrane in PD patients.

Cited by 17 publications

References 53 publications

Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

Histone deacetylase 6 inhibition counteracts the epithelial-mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis

Luteolin inhibits angiogenesis of the M2‑like TAMs via the downregulation of hypoxia inducible factor‑1α and the STAT3 signalling pathway under hypoxia

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