Transición epitelio-mesenquimal como diana terapéutica en modelos experimentales de diálisis peritoneal

Resumen

Peritoneal dialysis is a renal replacement strategy based on the use of the peritoneum as a semi-permeable membrane across which ultrafiltration and diffusion take place. During peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. The high concentration of glucose and glucose degradation products in standard peritoneal dialysis fluids induce a local diabetic environment, which leads to the formation of advanced glycation end products (AGEs) that have an important role in peritoneal membrane deterioration. The long-term exposure to the dialisys fluids causes an inflammation process and the epithelial-to-mesenchymal transition (EMT) of the mesothelial cells. This process is associated with peritoneal membrane failure. In this study we used a rat model and developed a mouse model of peritoneal dialysis that help us to test the inflammation and the EMT as therapeutic targets in the peritoneal deterioration caused by the peritoneal dialysis treatment. These animals model were accompanied with in vitro and ex vivo experiments, that serve us to know the molecular mechanism of the different therapeutic approach that we used. First of all, we study the role of Bone morphogenic protein-7 (BMP-7). This protein antagonizes transforming growth factor TGF-"#9 1+:78-*'/ ;<= -.: )&+*'(*/ -3-2./* fibrosis. Herein, we analyzed the modulating role of BMP-7 on EMT of mesothelial cells in vitro and its protective effects in a rat peritoneal dialysis model. The data point to a balance between BMP-7 and TGF-"# 2. *5' (+.*&+8 +0 ;<= -.: 2.:2(-*' *5-* >8+(?-:e of EMT may be a therapeutic approach to ameliorate peritoneal membrane damage during peritoneal dialysis. Because cyclooxygenase-2 (Cox-2) is induced by inflammation, we studied the role of Cox-2 in the deterioration of the peritoneal membrane. Herein, we demonstrate that Cox-2 is upregulated during the EMT of mesothelial cells and that peritoneal transport rate correlates with Cox-2 expression ex vivo. We also show that Cox-2 inhibition does not prevent EMT in vitro but ameliorates peritoneal membrane worsening in vivo in a mouse model of peritoneal dialysis fluid exposure. The data point to Cox-2 as key player in the setting and maintenance of peritoneal inflammation and reveal antiinflammatory therapy as a strategy to preserve peritoneal membrane integrity in patients in peritoneal dialysis. Peroxisome proliferator-activated receptor-% @AABC-%D -3+.2/*/ -&' 7/': *+ *&'-* *E)' FF diabetes and they have beneficial effects on inflammation, fibrosis, and angiogenesis. Hence, we evaluated the efficacy of the PPAR-% -3+.2/* &+/2382*-G+.' @CHID 2. ameliorating peritoneal membrane damage in a mouse peritoneal dialysis model, and we analyzed the mechanisms underlying the protection offered by RSG. According to the data, RSG appears to produce pleiotropic protective effects on the peritoneal membrane by reducing the accumulation of AGEs and inflammation, and by preserving the mesothelial cells monolayer, highlighting the potential of PPAR-% -(*2J-*2+. *+ ameliorate peritoneal deterioration in peritoneal dialysis patients. Transforming growth factor (TGF)-"1 is a well-characterized inducer of EMT and has been proposed to be a master molecule in PD fluid-induced peritoneal membrane deterioration. Hence, we evaluated the efficacy of TGF-"1 blocking peptides in modulating EMT in vitro and in vivo, and in ameliorating peritoneal damage in a mouse peritoneal dialysis model. The results demonstrate that TGF-"1 has a major role in the peritoneal deterioration induced by dialysis fluids and highlight TGF-"1-mediated EMT as key process in the patho-physiology of the peritoneal dysfunction.