Transgenic Mouse Models

Nishino, Tomoya; Ni, Jie; Devuyst, Olivier

doi:10.1177/089686080702700604

Cited by 8 publications

(4 citation statements)

References 56 publications

(78 reference statements)

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“…The structure of the visceral and parietal peritoneum is similar in humans, rats, and mice (Nishino et al , ), suggesting that experiments in genetically modified mice can provide valuable information about the damage associated with clinical PD. Here, we present what is to our knowledge the first analysis of the effect of PD‐fluid exposure in a genetically modified animal model.…”

Section: Discussionmentioning

confidence: 99%

Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

et al. 2014

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Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial–mesenchymal transition (EMT) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1−/− mice showed increased EMT, thickness, and fibrosis. Exposure of Cav1−/− mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP-1/cytokeratin-positive cells invading the sub-mesothelial stroma. High-throughput quantitative proteomics revealed increased abundance of collagens, FN, and laminin, as well as proteins related to TGF-β activity in matrices derived from Cav1−/− cells. Lack of Cav1 was associated with hyperactivation of a MEK-ERK1/2-Snail-1 pathway that regulated the Smad2-3/Smad1-5-8 balance. Pharmacological blockade of MEK rescued E-cadherin and ZO-1 inter-cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1−/− mice. Moreover, treatment of human PD-patient-derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re-acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD.

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Section: Discussionmentioning

confidence: 99%

Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

et al. 2014

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“…Low-grade PDF-induced chronic inflammation contributes significantly to progressive structural alterations of PM. 23,50 Under high-glucose conditions, inflammatory conditions, or both, PMCs produce proinflammatory mediators such as IL-6, MCP-1, IL-17, and tumor necrosis factor-a, 16,[51][52][53][54] which are important for peritoneal recruitment of inflammatory cells and fibrosis progression. 51 Since total PKC activity has been shown to be involved in this response, 16 we investigated whether PKCa is the PKC isoform responsible for proinflammatory mediator upregulation and for inflammatory cell influx.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate

Wang

Balzer

Rong

et al. 2016

Kidney International

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Chronic exposure to commercial glucose-based peritoneal dialysis fluids during peritoneal dialysis induces peritoneal membrane damage leading to ultrafiltration failure. In this study the role of protein kinase C (PKC) α in peritoneal membrane damage was investigated in a mouse model of peritoneal dialysis. We used 2 different approaches: blockade of biological activity of PKCα by intraperitoneal application of the conventional PKC inhibitor Go6976 in C57BL/6 wild-type mice and PKCα-deficient mice on a 129/Sv genetic background. Daily administration of peritoneal dialysis fluid for 5 weeks induced peritoneal upregulation and activation of PKCα accompanied by epithelial-to-mesenchymal transition of peritoneal mesothelial cells, peritoneal membrane fibrosis, neoangiogenesis, and macrophage and T cell infiltration, paralleled by reduced ultrafiltration capacity. All pathological changes were prevented by PKCα blockade or deficiency. Moreover, treatment with Go6976 and PKCα deficiency resulted in strong reduction of proinflammatory, profibrotic, and proangiogenic mediators. In cell culture experiments, both treatment with Go6976 and PKCα deficiency prevented peritoneal dialysis fluid-induced release of MCP-1 from mouse peritoneal mesothelial cells and ameliorated transforming growth factor-β1-induced epithelial-to-mesenchymal transition and peritoneal dialysis fluid-induced MCP-1 release in human peritoneal mesothelial cells. Thus, PKCα plays a crucial role in the pathophysiology of peritoneal membrane dysfunction induced by peritoneal dialysis fluids, and we suggest that its therapeutic inhibition might be a valuable treatment option for peritoneal dialysis patients.

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“…As for the genetically modified mice, both knockout and transgenic models have been used over the past few years in order to provide important information in many different molecular pathways that are significant for PD (Nishino et al, 2007 ). The ability to modify the genome of mice enabled the scientists to explore the expression of different genes and the results of the modification of their expression.…”

mentioning

confidence: 99%

Animal models in peritoneal dialysis

et al. 2015

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Peritoneal dialysis (PD) has been extensively used over the past years as a method of kidney replacement therapy for patients with end stage renal disease (ESRD). In an attempt to better understand the properties of the peritoneal membrane and the mechanisms involved in major complications associated with PD, such as inflammation, peritonitis and peritoneal injury, both in vivo and ex vivo animal models have been used. The aim of the present review is to briefly describe the animal models that have been used, and comment on the main problems encountered while working with these models. Moreover, the differences characterizing these animal models, as well as, the differences with humans are highlighted. Finally, it is suggested that the use of standardized protocols is a necessity in order to take full advantage of animal models, extrapolate their results in humans, overcome the problems related to PD and help promote its use.

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Transgenic Mouse Models

Cited by 8 publications

References 56 publications

Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate

Animal models in peritoneal dialysis

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