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New strategies for inflammation and peritoneal fibrosis blockade in chronic kidney disease: effect thalidomide, tamoxifen, BMP-7 and stem cell infusion

Grant number: 10/00054-5
Support type:Regular Research Grants
Duration: June 01, 2010 - November 30, 2012
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Irene de Lourdes Noronha
Grantee:Irene de Lourdes Noronha
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chronic kidney disease (CKD) is considered a public health problem worldwide. Peritoneal dialysis is a therapeutic option for the treatment of patients with CKD stage 5. However, long-term morphological and functional changes resulting from incompatible dialysis solutions and peritoneal infections can compromise the effectiveness of the peritoneal membrane. These changes occur progressively and are expressed clinically by the inefficiency of ultrafiltration and, histologically, by different degrees of inflammation, fibrosis and peritoneal sclerosis, leading to the failure of this modality of dialysis and increased morbidity and mortality in patients with CKD.The aim of this study is to analyze new strategies for blocking inflammation and peritoneal fibrosis in experimental CKD, in order to establish possible alternative treatments to this serious and limiting complication of the peritoneal dialysis. In addition, we aim to investigate the mechanisms of each proposed treatment, to elucidate its protective effects in the peritoneal tissue in CKD.To study the mechanisms involved in this process and to analyze the therapeutic strategies, an experimental model of peritonitis with peritoneal fibrosis in uremic CKD animals will be used, to mimic the events described above. The peritonitis will be induced by intraperitoneal injection of chlorhexidine gluconate. To induce a non-surgical uremic CKD model, we will use the adenine model, an innovative model of uremia not established in Brazil yet. The strategies to block inflammation and peritoneal fibrosis are: treatment with thalidomide, tamoxifen, BMP-7 (bone morphogenic protein-7) or stem cells (mesenchymal or derived from amniotic fluid). Thalidomide, tamoxifen and BMP-7 present anti-inflammatory, anti-angiogenic, anti-proliferative and anti-fibrotic properties, whereas the use of stem cells has been used because of its potential therapeutic effect of regenerative organs and tissues, besides its immunomodulatory activities. Considering that epithelial-mesenchymal transition (EMT) represents a crucial phenomenon to form fibrotic tissue from mesothelial cells, we will investigate whether the treatments have effect in the mechanisms of the EMT, specifically acting in mediators (TGF-², MMP, IL-18 e TNF-±) and in main signaling pathways of this process (Smads e JNK). (AU)