TGF-β1 Promotes Lymphangiogenesis during Peritoneal Fibrosis

Kinashi, Hiroshi; Ito, Yasuhiko; Mizuno, Masashi; Suzuki, Yoshio; Terabayashi, Takeshi; Nagura, Fumiko; Hattori, Ryohei; Matsukawa, Yoshihisa; Mizuno, Tomohiro; Noda, Yukihiro; Nishimura, Hayato; Nishio, Ryo; Maruyama, Shoichi; Imai, Enyu; Matsuo, Seiichi; Takei, Yoshiyuki

doi:10.1681/asn.2012030226

Cited by 71 publications

(131 citation statements)

References 60 publications

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“…[5][6][7]23,24 The antibodies used are listed in Supplementary Table 1. Mast cells were evaluated using sections stained with 0.2% toluidine blue.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

“…RNA preparation and the synthesis of first-strand cDNA were performed as described previously. [5][6][7]23,24 Total RNA (1 μg) was then reverse transcribed. Quantitative real-time PCR (qPCR) analysis was performed with an Applied Biosystems (South San Francisco, CA, USA) Prism 7500HT sequence detection system using TaqMan gene expression assays as described previously.…”

Section: Rna Preparation From Peritoneal and Diaphragmmentioning

confidence: 99%

“…18S ribosomal RNA was used as an endogenous control. 5,7,23,24 Assessment of Lymphatic Absorption To assess absorption via the lymphatic vessels, animals that received 2000 μl of 7.5% icodextrin peritoneal dialysis solution into the peritoneal cavity were killed at 4 h after infusion. An accurate drained volume was measured.…”

Section: Rna Preparation From Peritoneal and Diaphragmmentioning

confidence: 99%

“…5 Furthermore, VEGF-C expression and lymphangiogenesis were suppressed by the TGFβRI inhibitor or by the cyclooxygenase-2 (COX-2) inhibitor, celecoxib, in chlorhexidine gluconate-induced peritoneal injury models. 5 Thus, we proposed that lymphangiogenesis in the peritoneal membrane, similar to renal fibrosis is linked with the fibrotic process via the TGF-β-VEGF-C pathway. [6][7][8] The lymphatic absorption rate, which is measured by the rate at which intraperitoneally administered radioactive serum albumin or the macromolecule dextran 70 disappears, is significantly higher in patients with ultrafiltration failure, and lymphatic absorption is considered to be one of the causes of the decrease in net ultrafiltration.…”

mentioning

confidence: 99%

“…5 In cultured mesothelial cells and macrophages, TGF-β-induced VEGF-C expression was blocked by a TGF-β type I receptor (TGFβRI) inhibitor. 5 Furthermore, VEGF-C expression and lymphangiogenesis were suppressed by the TGFβRI inhibitor or by the cyclooxygenase-2 (COX-2) inhibitor, celecoxib, in chlorhexidine gluconate-induced peritoneal injury models. 5 Thus, we proposed that lymphangiogenesis in the peritoneal membrane, similar to renal fibrosis is linked with the fibrotic process via the TGF-β-VEGF-C pathway.…”

mentioning

confidence: 99%

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Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury

Terabayashi

Ito

Mizuno

et al. 2015

Laboratory Investigation

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“…[5][6][7]23,24 The antibodies used are listed in Supplementary Table 1. Mast cells were evaluated using sections stained with 0.2% toluidine blue.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Section: Rna Preparation From Peritoneal and Diaphragmmentioning

confidence: 99%

Section: Rna Preparation From Peritoneal and Diaphragmmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury

Terabayashi

Ito

Mizuno

et al. 2015

Laboratory Investigation

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Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Ruliffson

Whittington

2023

Advanced Biology

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Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis‐related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis‐related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease—enabled through more accurate preclinical modeling—will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients.

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Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis

Shi

Tao

Wang

et al. 2019

The Journal of Pathology

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Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3-deazaneplanocin A (3-DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long-term PD patients, which was positively correlated with expression of TGF-1, vascular endothelial growth factor, and IL-6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3-DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF-1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor-B phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3-DZNeP effectively improved high glucose PDF-associated peritoneal dysfunction by decreasing the dialysate-to-plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2 h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3-DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase-2 and -9. Finally, EZH2-KO mice exhibited less peritoneal fibrosis than EZH2-WT mice. In HPMCs, treatment with EZH2 siRNA or 3-DZNeP suppressed TGF-1-induced upregulation of -SMA and Collagen I and preserved E-cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis.

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TGF-β1 Promotes Lymphangiogenesis during Peritoneal Fibrosis

Cited by 71 publications

References 60 publications

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury

Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling

Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis

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