Tamoxifen Ameliorates Peritoneal Membrane Damage by Blocking Mesothelial to Mesenchymal Transition in Peritoneal Dialysis

Abstract

Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process.

Is there an end in Sight for Encapsulating Peritoneal Sclerosis?

“…Several studies have demonstrated that tamoxifen may influence the epithelialto-mesenchymal transition and fibrosis of mesothelial cells (9). Should there be more widespread adoption of the protocol described by De Sousa?…”

Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models

“…Daily intraperitoneal exposure of 1.5-3.0 ml of 4.25% glucose PDF for 4 or 5 weeks, with or without implanting a catheter, produced peritoneal dysfunction and morphological changes, such as fibrosis and neoangiogenesis, in mice [78][79][80][81][82][83].…”

“…Other models of non-infectious peritoneal injury associated with inflammation and fibrosis Administration of PDF into the abdominal cavity of rats and mice by repeated intraperitoneal injection or implanting a catheter is a method used to study the pathophysiological changes of the peritoneum associated with PD [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83], but a non-peritonitis model. Daily intraperitoneal injection of 4.25% glucose dialysate into the rat abdominal cavity for 1 week induced an increased peritoneal membrane transport rate and the absence of the peritoneal surface layer, as observed by electron microscopy [69,70].…”

Análise do efeito do Tamoxifeno e da BMP-7 em modelo experimental de fibrose peritoneal em ratos com doença renal crônica

“…Diferente de modelos de lesões renais crônicas em que a melhora da lesão renal está associada a maior expressão de VEGF e consequente maior vascularização, no caso da fibrose peritoneal este fator de crescimento está relacionado à inflamação, neoangiogênese, perda da capacidade de ultrafiltração e a fibrose da membrana peritoneal [Pecoits-Filho R et al, 2002]. Neste sentido, estudos experimentais de fibrose peritoneal demonstraram que a menor expressão de VEGF e α-actina está relacionada ao bloqueio da diferenciação de células mesoteliais em miofibroblastos e fibroblastos [Loureiro J et al, 2013;Loureiro J et al, 2010]. Estabelecendo um paralelo a estes dados, Hong Guo e colaboradores associaram o modelo de fibrose peritoneal induzido por solução de diálise ao modelo de nefrectomia 5/6 que provoca um estado de uremia não tão severo quanto ao modelo adenina [Guo H et al, 2007].…”

“…Uma série de estudos em modelos experimentais diferentes apontam que o principal mecanismo anti-fibrótico do TAM e da BMP7 estão relacionados com o bloqueio da via TGF-β/SMAD [Loureiro J et al, 2013;Loureiro J et al, 2010;Dellê H et al, 2012;Zeisberg M et al, 2003]. …”