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      Characterization of Adenosine Receptors in Human Kidney Proximal Tubule (HK-2) Cells

      ,

      Cardiorenal Medicine

      S. Karger AG

      G proteins, Mitogen-activated protein kinase, Cyclic AMP, Adenylyl cyclase

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          Abstract

          Renal proximal tubule cells are particularly vulnerable to injury following ischemia and reperfusion due to their marginal blood supply and high metabolic demand. Renal adenosine receptor (AR) modulations preserve renal function following ischemic-reperfusion injury in vivo. Numerous intracellular proteins have been shown to be pivotal in the signal transduction of adenosine-mediated protection in vivo. However, characterization of the expression and function of ARs and intracellular proteins mediating protection in human proximal tubular cells is lacking. Therefore, we studied the ARs in an immortalized human renal proximal tubular cell (HK-2) line to determine if this cell line could function as an in vitro model of AR coupling. Immunoblotting with AR subtype specific antibodies detected all 4 subtypes of ARs (A<sub>1</sub>, A<sub>2a</sub>, A<sub>2b</sub> and A<sub>3</sub>), several isoforms of protein kinase C (α, δ, and Ε and several heterotrimeric G-protein isoforms (G<sub>i</sub>α, G<sub>s</sub>α and G<sub>q</sub>α). The A<sub>1</sub> and A<sub>3</sub> ARs inhibited forskolin- stimulated adenylyl cyclase activity. The A<sub>1</sub> ARs also activated 42/44-kD ERK mitogen-activated protein kinases via G<sub>i</sub>- and tyrosine kinase-dependent pathways. The A<sub>2a</sub> ARs stimulated adenylyl cyclase activity and activated the protein kinase A→CREB pathway. Chronic (48 h) treatment with a nonselective AR antagonist (8-phenyltheophylline) upregulated A<sub>1</sub>, A<sub>2a</sub> ARs and G<sub>i</sub>α. Conversely, chronic stimulation of HK-2 ARs with a nonselective AR agonist (N-ethylcarbamoyladenosine) downregulated all 4 subtypes of ARs and G<sub>s</sub>α. Based on these findings, HK-2 cells are a useful in vitro model to study the signaling cascades of AR-mediated renal protection.

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          Most cited references 2

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          Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts.

           G A Cordis,  Y Zu,  M Watanabe (1996)
          While much is known about the beneficial effects of myocardial stress adaptation, relatively less information is available about the adaptive mechanisms. To explore the signaling pathways of stress adaptation, isolated working rat hearts were divided into three groups. Group I was adapted to stress by conventional technique of repeated ischemia and reperfusion consisting of 5 min of ischemia followed by 10 min of reperfusion, repeated four times. Group II was treated with 100 microM of genistein, a tyrosine kinase inhibitor, followed by preconditioning as described for group I. The third group, perfused with buffer only for 60 min, served as control. All hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. The results of our study demonstrated better postischemic myocardial functions in the preconditioned hearts as evidenced by increased aortic flow, coronary flow, developed pressure and lesser amount of tissue injury as evidenced by the decreased creatine kinase release. The preconditioning effects were associated with enhancement of phospholipase D activity in the heart. The preconditioning effect was almost abolished by the genistein treatment which also prevented the enhancement of phospholipase D activities. Additionally, preconditioning of the rat hearts stimulated protein kinase C, MAP kinase, and MAPKAP kinase 2 activities which were inhibited by genistein. The results identifies for the first time tyrosine kinase-phospholipase D as potential signaling pathway for ischemic preconditioning, and implicates the involvement of multiple protein kinases in myocardial adaptation to ischemia.
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            Desensitization of normal rat kidney cells to adenosine

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              Author and article information

              Journal
              EXN
              Nephron Exp Nephrol
              10.1159/issn.1660-2129
              Cardiorenal Medicine
              S. Karger AG
              1660-2129
              2002
              2002
              09 October 2002
              : 10
              : 5-6
              : 383-392
              Affiliations
              Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, N.Y., USA
              Article
              65306 Exp Nephrol 2002;10:383–392
              10.1159/000065306
              12381923
              © 2002 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: 27, Pages: 10
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/65306
              Categories
              Original Paper

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