Paricalcitol Reduces Peritoneal Fibrosis in Mice through the Activation of Regulatory T Cells and Reduction in IL-17 Production

González-Mateo, Guadalupe; Fernández-Míllara, Vanessa; Bellón, Teresa; Liappas, Georgios; Ruíz-Ortega, Marta; López–Cabrera, Manuel; Selgas, Rafael; Aroeira, Luiz S.

doi:10.1371/journal.pone.0108477

Cited by 56 publications

(56 citation statements)

References 43 publications

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“…Gonzalez-Mateo et al (13) did not find a significant increase in peritoneal fluid TGF-β, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IFN-γ and TNF-α levels similar to our study when they evaluated the effect of paricalcitol on the fibrotic process in mice which undergoing peritoneal dialysis. They only found a statistically significant difference in IL-17 levels as paricalcitol reduced the IL-17 level in peritoneal fluid.…”

Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permsupporting

confidence: 89%

“…The interstitial extracellular matrix accumulation was also significantly reduced by treatment with paricalcitol. Gonzalez-Mateo et al (13) similarly showed that paricalcitol co-treatment significantly decreased peritoneal membrane thickness in rats that had undergone peritoneal dialysis. We found a correlation between increasing doses of paricalcitol co-treatment and decreased peritoneal membrane thickness.…”

Section: Türk Nefroloji Diyaliz Ve Transplantasyon Dergisi Turkish Nementioning

confidence: 96%

“…They only found a statistically significant difference in IL-17 levels as paricalcitol reduced the IL-17 level in peritoneal fluid. Gonzalez-Mateo et al (13) suggested at the end of the study that TGF-β was regulated by IL-17 and may be a target for blocking fibrosis.…”

Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permmentioning

confidence: 99%

“…The authors did not evaluate the effects of ultrafiltration in this study. Gonzalez-Mateo et al (13) showed that a significant level of ultrafiltration loss was experienced in the group receiving PD only compared to the group receiving paricalcitol co-treatment. However, the authors did not evaluate the permeability parameters of the peritoneal membrane in this study either.…”

Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permmentioning

confidence: 99%

“…It has also been shown to inhibit fibrosis in obstructive nephropathy and inhibit EMT in renal tubular cells (11). Paricalcitol has been reported to block EMT, a key mechanism of peritoneal fibrosis, in two important recent studies (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Paricalcitol Protects Peritoneal Membrane Function in Encapsulating

Gül¹,

Yıldız²,

Vuruşkan³

et al. 2016

Turk Neph Dial Transpl

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OBJECTIVE:The most lethal complication of peritoneal dialysis is encapsulating peritoneal sclerosis (EPS), which develops as a result of epithelio-mesenchymal transformation (EMT) and known fibrotic processes. Paricalcitol has previously been shown to inhibit both EMT and fibrosis. We investigated the effect of paricalcitol on EPS. MATERIAL and METHODS:Forty non-uremic albino Wistar rats divided into four groups of equal numbers. The first group was administered 2 mL saline intraperitoneally (IP) and the second group was administered 2 mL of 200 gram chlorhexidine gluconate (CG) (0.1%) dissolved in saline and ethanol (15%) IP. The treatment groups received CG for three weeks in addition to subcutaneous paricalcitol at a dose of 0.2 mcg/kg/day to the third group and 0.4 mcg/kg/day to the fourth group. A one-hour peritoneal equilibration test was performed with 25 mL 3.86% PD solution at the end of the study. Peritoneal membrane and intracardiac blood samples were obtained.RESULTS: D/P urea was significantly low in both treatment groups when compared to group 2 (p<0.05). Paricalcitol co-treatment recovered ultrafitration failure and peritoneal membrane thickness was better paricalcitol groups but there was no statistically significant difference between the groups. Serum calcium, phosphorus and parathyroid hormone levels were similar in all groups. CONCLUSION:Paricalcitol can be effective in the protection of peritoneal functions.KEy wORDS: Paricalcitol, Encapsulating peritoneal sclerosis, Peritoneal membrane permeability, Ultrafiltration failure, Peritoneal membrane function Öz AMAÇ: Periton diyalizinin en öldürücü komplikasyonu olan enkapsüle peritoneal sklerozis (EPS), epithelio-mezenkimal dönüşüm (EMT) ve bilinen fibrotik süreçlerinin bir sonucunda meydana gelir. Parikalsitolün EMT' yi engellediği ve antifibrotik özelliklerinin olduğu gösterilmiştir. Çalışmanın amacı, deneysel EPS modeli üzerinde parikalsitolün etkisini araştırmaktır. GEREÇ ve yÖNTEMLER:Kırk adet üremik olmayan 200-220 gram ağırlığında, albino wistar cinsi, dişi sıçan kullanıldı. Sıçanlar rastgele eşit sayıda dört gruba ayrıldı. Üç hafta süreyle birinci gruba intraperitoneal (İP) 2 mL serum fizyolojik verildi, ikinci gruba 2 mL/ 200 gram serum fizyolojik içinde çözünmüş klorheksidin glükonat (KG) (%0,1) ve etanol (%15) İP verildi. Üçüncü ve dördüncü gruba üç hafta boyunca KG ile birlikte sırasıyla 0,2 mcg/kg/gün ve 0,4 mcg/kg/gün derialtı parikalsitol yapıldı. Çalışma sonunda, tüm gruplara 1 saatlik 25mL %3,86 PD solüsyonu ile periton eşitleme testi yapıldı. Peritoneal sıvı, intrakardiyak kan örnekleri elde edildi ve patolojik inceleme için peritonun İP uygulama yapılmayan tarafı alındı. TGF-β1 düzeyi periton sıvısından çalışıldı.BULGULAR: D/P üre parikalsitol alan gruplarda grup 2 ile karşılaştırıldığında belirgin olarak daha düşüktü (p<0,05). Parikalsitol tedavisi doz bağımlı olarak ultrafiltrasyon kaybını azalttı, aynı zamanda parikalsitol alan sıçanlarda periton kalınlığı daha azdı. Ancak bu iki bulguda istatiksel olarak anlamlılı...

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Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permsupporting

confidence: 89%

Section: Türk Nefroloji Diyaliz Ve Transplantasyon Dergisi Turkish Nementioning

confidence: 96%

Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permmentioning

confidence: 99%

Section: Figure 1: Effects Of Paricalcitol Therapy On Peritoneal Permmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Paricalcitol Protects Peritoneal Membrane Function in Encapsulating

Gül¹,

Yıldız²,

Vuruşkan³

et al. 2016

Turk Neph Dial Transpl

View full text Add to dashboard Cite

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Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

et al. 2016

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Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial-to-mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post-surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT-PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor-beta (TGF-β) pathway. The severity of adhesions and MMT-related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT-related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF-β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents.

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Mesothelial‐to‐mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer

Rynne-Vidal

Au‐Yeung

Jiménez‐Heffernan

et al. 2017

The Journal of Pathology

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111

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Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted into carcinoma‐associated fibroblasts (CAFs) through mesothelial‐to‐mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT‐related pathways – including transforming growth factor (TGF)‐β signalling – are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients. In a mouse model, pre‐induction of MMT resulted in increased peritoneal tumour growth, whereas interfering with the TGF‐β receptor reduced metastasis. MC‐derived CAFs showed activation of Smad‐dependent TGF‐β signalling, which was disrupted in OvCa cells, despite their elevated TGF‐β production. Accordingly, targeting Smad‐dependent signalling in the peritoneal pre‐metastatic niche in mice reduced tumour colonization, suggesting that Smad‐dependent MMT could be crucial in peritoneal carcinomatosis. Together, these results indicate that bidirectional communication between OvCa cells and MC‐derived CAFs, via TGF‐β‐mediated MMT, seems to be crucial to form a suitable metastatic niche. We suggest MMT as a possible target for therapeutic intervention and a potential source of biomarkers for improving OvCa diagnosis and/or prognosis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Paricalcitol Reduces Peritoneal Fibrosis in Mice through the Activation of Regulatory T Cells and Reduction in IL-17 Production

Cited by 56 publications

References 43 publications

Paricalcitol Protects Peritoneal Membrane Function in Encapsulating

Paricalcitol Protects Peritoneal Membrane Function in Encapsulating

Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions

Mesothelial‐to‐mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer

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