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      Angiotensin-Converting Enzyme Inhibition Induces Death Receptor Apoptotic Pathways in Erythroid Precursors following Renal Transplantation

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          Abstract

          Background: Posttransplant erythrocytosis (PTE) is a condition that occurs in kidney transplant patients and is characterized by increase in hematocrit above 51%. While its pathogenesis remains unclear, angiotensin-converting enzyme inhibitors (ACEI) have been used successfully in the treatment of PTE. We have previously shown that ACEI induce apoptosis in the peripheral erythroid precursors from patients with PTE. In the current study we elucidate the molecular mechanisms of ACEI-induced apoptosis. Methods: Peripheral CD34+ cells were obtained from four normal controls, five normal kidney transplants, and six kidney transplants with PTE, before and after treatment with ACEI. We evaluated the expression of a variety of apoptotic factors by quantitative reverse transcription-multiplex polymerase chain reaction, Western blot and immunocytochemistry. Results: ACEI resulted in a significant induction of Fas, FADD, and TRADD mRNAs in renal transplant patients with or without PTE. No changes were noted in the expression of mRNAs encoding Bcl-2, Bcl-xL, Bax, caspase 8, caspase 3, or GAPDH. ACEI also resulted in a significant upregulation of Fas, FADD and TRADD protein expression, and their localization predominantly at the plasma membrane. Conclusions: Our results suggest that ACEI therapy induces apoptosis in erythrocyte progenitor cells of renal transplant patients at least in part via induction of death receptor apoptotic cascades.

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          Most cited references 4

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          Autocrine T-cell suicide mediated by APO-1/(Fas/CD95)

          The APO-1/(Fas/CD95) cell surface receptor is a member of the nerve growth factor (NGF)/tumour necrosis factor (TNF) receptor superfamily and mediates apoptosis. Peripheral activated T cells (ATC) from lymphoproliferation (lpr/lpr) mutant mice that express a reduced number of APO-1 receptors have a defect in T-cell receptor (TCR)-induced apoptosis. This suggests that TCR-induced apoptosis involves APO-1. We tested this hypothesis in various human T cells: (1) malignant Jurkat cells, (2) an alloreactive T-cell clone (S13), and (3) peripheral ATC. TCR triggering through immobilized anti-CD3 antibodies or Staphylococcus enterotoxin B (SEB) superantigen induced expression of the APO-1 ligand and apoptosis in these cells. Anti-CD3-induced apoptosis of Jurkat cells was demonstrated even in single-cell cultures. In all cases apoptosis was substantially inhibited by blocking anti-APO-1 antibody fragments and soluble APO-1 receptor decoys. The APO-1 ligand was found in the supernatant of activated Jurkat cells as a soluble cytokine. We propose that TCR-induced apoptosis in ATC can occur through an APO-1 ligand-mediated autocrine suicide. These results provide a mechanism for suppression of the immune response and for peripheral tolerance by T-cell deletion.
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            Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats.

            Tubular atrophy is a major feature of most renal diseases and is closely associated with loss of renal function. The present study sought to investigate tubular epithelial cell apoptosis in experimental diabetic nephropathy and to explore the role of pro-apoptotic [transforming growth factor-beta (TGF-beta) and anti-apoptotic growth factors [epidermal growth factor (EGF)]. The effects of renoprotective therapy with blockade of the renin-angiotensin system (RAS) also were examined. Six-week-old female Ren-2 rats were injected with streptozotocin (STZ) and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme (ACE) inhibitor, perindopril, or the angiotensin II type 1 (AT1) receptor antagonist, valsartan, for 12 weeks. Widespread apoptosis, identified immunohistochemically by single stranded DNA and TUNEL, was noted in the tubules of diabetic Ren-2 rats. These changes were associated with a 50% decrease in EGF expression and a twofold increase in TGF-beta1 mRNA. Treatment of diabetic Ren-2 rats with either valsartan (20 mg/kg/day) or perindopril (6 mg/kg/day) reduced apoptosis to control levels in association with supranormal levels of EGF mRNA (P < 0.01) and a reduction in TGF-beta1 gene expression (P < 0.05) to that of control rats. Tubular apoptosis is a prominent feature of diabetic Ren-2 rats that is attenuated by blockade of the RAS in association with modulation of pro- and anti-apoptotic growth factor expression.
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              INTERFERENCE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS ON ERYTHROPOIESIS IN KIDNEY TRANSPLANT RECIPIENTS

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2003
                August 2003
                31 July 2003
                : 23
                : 4
                : 195-201
                Affiliations
                Divisions of aNephrology and cHematology, Albert Einstein College of Medicine, Bronx, N.Y., and bNephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
                Article
                71188 Am J Nephrol 2003;23:195–201
                10.1159/000071188
                12748417
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. 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
                Figures: 5, Tables: 1, References: 24, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/71188
                Categories
                Original Article: Patient-Oriented, Translational Research

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