0
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Regulation of Plasma Hemopexin Activity by Stimulated Endothelial or Mesangial Cells

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The pathogenesis of glomerular alterations and proteinuria in corticosteroid-responsive nephrotic syndrome (CRNS) is unknown. As an isoform of plasma hemopexin (Hx) with protease activity may be implicated in this disease, we have studied the inhibition of Hx by ADP and reactivation to its active form by endothelial or mesangial cells in vitro. We hypothesized that these cells might potentially be able to convert the inactivated form of Hx (Hxi) to active Hx (Hxa) in vitro, mediated by cellular ecto-ADPase. Since ecto-ADPase (CD39) is upregulated after stimulation of these cells with lipopolysaccharide (LPS) or certain cytokines, we postulated that this conversion might occur specifically after inflammatory stimulation of these cells. Human endothelial or mesangial cell cultures were incubated overnight with or without LPS (10.0 ng/ml) or TNFα (10.0 ng/ml), washed and subsequently incubated with Hxi (1.5 mg/ml) in serum-free conditions (Hxi was prepared by treatment of Hxa with ADP or ADP-β-S). After 60 min, supernatants were tested for their capacity to alter glomerular extracellular matrix molecules (i.e. ecto-apyrase) in vitro using standard methods, and compared with Hxi that had not been incubated with cells. Supernatants containing Hxa (1.5 mg/ml) served as positive control. The results show significant activity in supernatants with Hxi (prepared using native ADP). However, Hxi inactivated by ADP-β-S (which is non-hydrolyzable) could not be reactivated after contact with LPS-stimulated or unstimulated cells in vitro. As ecto-ADPase of these cells is upregulated by LPS, we believe that reactivation of Hxi to Hxa is mediated by cellular ecto-ADPase. Although the relevance of this inflammation-mediated activation mechanism of Hx in patients with CRNS requires further experimentation, our preliminary observations suggesting that this mechanism is corticosteroid dependent may support a potential role of Hxa in CRNS.

          Related collections

          Most cited references 11

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of the platelet ADP receptor targeted by antithrombotic drugs.

          Platelets have a crucial role in the maintenance of normal haemostasis, and perturbations of this system can lead to pathological thrombus formation and vascular occlusion, resulting in stroke, myocardial infarction and unstable angina. ADP released from damaged vessels and red blood cells induces platelet aggregation through activation of the integrin GPIIb-IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that potentiates the actions of many platelet activators. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes. The P2Y1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation. The second ADP receptor required for aggregation (variously called P2Y(ADP), P2Y(AC), P2Ycyc or P2T(AC)) is coupled to the inhibition of adenylyl cyclase through Gi. The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.

            Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome.

              Among patients with the idiopathic nephrotic syndrome who have focal and segmental glomerulosclerosis and undergo renal transplantation, 15 to 55 percent have recurrent nephrotic syndrome. The recurrence may be caused by a plasma factor or factors that increase glomerular permeability, because plasma exchange transiently decreases or abolishes proteinuria in some patients. We studied the effect on proteinuria of the removal of protein (mostly immunoglobulins) by adsorption onto protein A from the plasma of patients with recurrent nephrotic syndrome. Eight patients were treated with one to three cycles of two to seven 1-day sessions of protein adsorption, and the patients' urinary protein excretion was measured repeatedly. Their immunosuppressive regimens were not changed during the treatment. The adsorbed proteins were eluted from the protein A and injected into rats, and the urinary albumin excretion of the rats was measured. The protein-adsorption treatment consistently decreased urinary protein excretion by an average of 82 percent at the end of a cycle (P < 0.001). In one patient proteinuria disappeared, and in another urinary protein excretion remained below 2.5 g per day with repeated cycles of protein adsorption. In all but one patient the effect of adsorption was limited in time, with a return to the preadsorption level of protein excretion within a maximum of two months. The administration to rats of material eluted from the protein A increased urinary albumin excretion 2.9- to 4.6-fold (P < 0.001 and P = 0.005, respectively). Although protein A primarily binds immunoglobulins, the active fraction of the eluted proteins had a molecular weight below 100,000, indicating that immunoglobulin was not directly involved. Adsorption of plasma protein decreases urinary protein excretion in patients with recurrence of the nephrotic syndrome after renal transplantation. Studies of the adsorbed proteins should provide information about the mechanism of this disease.
                Bookmark

                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2004
                January 2004
                02 February 2004
                : 96
                : 1
                : p1-p10
                Affiliations
                Departments of aPathology and Laboratory Medicine, and bPharmacokinetics and Drug Delivery, University of Groningen, Groningen, The Netherlands; cNephrological Center, Medical Policlinic, Ludwig-Maximilians University, Munich, Germany
                Article
                75574 Nephron Physiol 2004;96:p1–p10
                10.1159/000075574
                14752238
                © 2004 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: 8, References: 48, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/75574
                Categories
                Original Paper

                Comments

                Comment on this article