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      Cysteinyl 1 Receptor Antagonist Montelukast, Does Not Prevent Peritoneal Membrane Damage in Experimental Chronic Peritoneal Dialysis Model in Rats

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          Abstract

          Background/Aims: Continuous ambulatory peritoneal dialysis (CAPD) induces structural changes in the peritoneal membrane such as fibrosis, vasculopathy and angioneogenesis with a reduction in ultrafiltration capacity. Leukotriene (LT) receptor antagonists have been found to be effective to prevent fibrosis in some nonperitoneal tissues. The aim of this study is to investigate the possible beneficial effect of montelukast, a LT receptor antagonist, on peritoneal membrane exposed to hypertonic peritoneal dialysis in uremic rats. Methods: Of the 48 male, 5/6 nephrectomized Wistar rats 29 remained alive and were included in the study. These studied rats were divided into 3 groups: Group I (n=7) was the control group, Group II (n=8) was treated with 20 ml hypertonic PDF intraperitoneally daily and Group III was treated with montelukast and similar PDF treatment protocol. The morphological and functional changes in the peritoneal membrane as well as cytokine expression were compared between groups. Results: Submesothelial thickness and the severity of the degree of hyaline vasculapathy were more prominent in group III when compared to group I. There were no significant differences between group II and other groups in terms of submesothelial thickness and the severity of the degree of hyaline vasculapathy. Increased expressions of TGF-β and VEGF in parietal peritoneal membrane were found in group II and group III when compared to group I. The amount of TGF-β and VEGF expression were similar in group II and group III. Conclusion: This study suggests that montelukast treatment does not prevent the peritoneal membrane from deleterious effects of hyperosmolar PDF in the uremic environment.

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          Most cited references 16

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          A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis.

          Leukotriene B4 (LTB4) is a potent chemoattractant that is primarily involved in inflammation, immune responses and host defence against infection. LTB4 activates inflammatory cells by binding to its cell-surface receptor (BLTR). LTB4 can also bind and activate the intranudear transcription factor PPAR alpha, resulting in the activation of genes that terminate inflammatory processes. Here we report the cloning of the complementary DNA encoding a cell-surface LTB4 receptor that is highly expressed in human leukocytes. Using a subtraction strategy, we isolated two cDNA clones (HL-1 and HL-5) from retinoic acid-differentiated HL-60 cells. These two clones contain identical open reading frames encoding a protein of 352 amino acids and predicted to contain seven membrane-spanning domains, but different 5'-untranslated regions. Membrane fractions of Cos-7 cells transfected with an expression construct containing the open reading frame of HL-5 showed specific LTB4 binding, with a K(d) (0.154nM) comparable to that observed in retinoic acid-differentiated HL-60 cells. In CHO cells stably expressing this receptor, LTB4 induced increases in intracellular calcium, D-myo-inositol-1,4,5-triphosphate (InsP3) accumulation, and inhibition of adenylyl cyclase. Furthermore, CHO cells expressing exogenous BLTR showed marked chemotactic responses towards low concentrations of LTB4 in a pertussis-toxin-sensitive manner. Our findings, together with previous reports, show that LTB4 is a unique lipid mediator that interacts with both cell-surface and nuclear receptors.
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            The pathophysiology of the peritoneal membrane.

            The development of peritoneal dialysis (PD) as a successful therapy has and still depends on experimental models to test and understand critical pieces of pathophysiology. To date, the majority of studies performed in rat and rabbit models derive mechanistic insights primarily on the basis of interventional pharmacologic agents, blocking antibodies, or transient expression systems. Because body size no longer limits the performance of in vivo studies of PD, genetic mouse models are increasingly available to investigate the molecular and pathophysiologic mechanisms of the peritoneal membrane. We illustrate in this review how these investigations are catching up with other areas of biomedical research and provide direct evidence for understanding transport and ultrafiltration, responses to infection, and structural changes including fibrosis and angiogenesis. These studies are relevant to mechanisms responsible not only for the major complications of PD but also for endothelial biology, host defense, inflammation, and tissue repair processes.
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              Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate.

              It has been speculated that increased levels of circulating or intraperitoneal pro-inflammatory cytokines such as interleukin 6, and pro-angiogenic vascular endothelial growth factor (VEGF) may contribute to high peritoneal small-solute transport rate (PSTR) in continuous ambulatory peritoneal dialysis (CAPD) patients. In this study we evaluated possible relationships between plasma and dialysate IL-6 and VEGF levels and PSTR. Forty CAPD patients (mean age+/-SD of 58+/-14 years) with no apparent inflammation process or disease, who had been on CAPD for 19+/-15 months (range 3-56 months) were included in the study. Peritoneal equilibration test (PET) was used to evaluate PSTR. Patients were divided into two groups: high-average and high transporters (H/A; D/P(creat)>/=0.65) and low-average and low transporters (L/A; D/P(creat)<0.64). Albumin and IgG clearances were used in the evaluation of permeability to larger solutes. Plasma and overnight dialysate levels of IL-6 and VEGF were measured. Plasma IL-6 (7.6 vs 4.3 pg/ml) and VEGF (342 vs 163 pg/ml) as well as dialysate IL-6 (174 vs 80 pg/ml) and VEGF (96 vs 69 pg/ml) levels were significantly higher in the H/A than in the L/A group. The dialysate appearance of IL-6 and VEGF correlated with D/P(creat), as well as with albumin and IgG clearances. Moreover, significant correlations were noted between dialysate IL-6 and dialysate VEGF levels. The findings of (i) increased plasma and dialysate levels of IL-6 and VEGF in the H/A group compared to the L/A group, (ii) an association between PSTR and both plasma and dialysate IL-6 and VEGF levels, and (iii) a significant correlation between dialysate IL-6 and VEGF concentrations suggest that inflammation, angiogenesis, and peritoneal transport may be interrelated and involved in the pathophysiology of high PSTR in CAPD patients. However, due to the cross-sectional design of this study, the cause and effect relationships between plasma and dialysate IL-6 and VEGF concentrations and high PSRT remain unclear.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2014
                December 2014
                19 December 2014
                : 39
                : 6
                : 648-657
                Affiliations
                aDivision of Nephrology, Department of Medicine, Bakırköy Dr. Sadi Konuk Training and Research Hospital; b Department of Nephrology, Marmara University School of Medicine; cDivision of Pediatric Urology, Department of Pediatric Surgery, Marmara University School of Medicine, Istanbul; dAtaturk Training and Research Hospital, Department of Pathology, İzmir; eDepartment of Nephrology, Marmara University School of Medicine; fDepartment of Nephrology, Academic Hospital; gDepartment of Nephrology, Marmara University School of Medicine, Istanbul, Turkey
                Author notes
                *Dr Sibel Yucel Kocak, Bakırköy Dr. Sadi Konuk Training and Research Hospital, Hemodiyaliz Unitesi Tevfik, Sağlam Cad. No:11, 34147 Zuhuratbaba Istanbul (Turkey), Tel. 00905055830860, E-Mail fsibelkocak@yahoo.com
                Article
                368477 Kidney Blood Press Res 2014;39:648-657
                10.1159/000368477
                25571878
                © 2015 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Pages: 10
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Peritoneal dialysis, Peritoneal membrane, Montelukast, Cytokines

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