A New Mesangial Triumvirate: Sulfonylureas, Their Receptors and Endosulfines

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Abstract

Although sulfonylureas have long been therapeutically utilized for their hypoglycemic properties in type 2 diabetic patients, there is a paucity of clinical or experimental data that suggests that this pharmacotherapeutic class confers a benefit on the course of diabetic renal disease. Because the mesangial compartment is central to the fibrogenic response that evolves during the course of diabetic nephropathy, determining the metabolic influence of sulfonylureas on mesangial cells is important. In this article, the current knowledge regarding the metabolic and functional consequences of a mesangial triumvirate of sulfonylureas, their sulfonylurea receptors and sulfonylurea-like ligands termed endosulfines will be reviewed.

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A view of sur/KIR6.X, KATP channels.

Alan J Bryan, O. Babenko, Courtney L. Bryan (1997)

ATP-sensitive potassium channels, termed KATP channels, link the electrical activity of cell membranes to cellular metabolism. These channels are heteromultimers of sulfonylurea receptor (SUR) and KIR6.X subunits associated with a 1:1 stoichiometry as a tetramer (SUR/KIR6.X forms the pores, whereas SUR regulates their activity. Changes in [ATP]i and [ADP]i gate the channel. The diversity of KATP channels results from the assembly of SUR and KIR6.X subtypes KIR6.1-based channels differ from KIR6.2 channels mainly by their smaller unitary conductance. SUR1- and SUR2-based channels are distinguished by their differential sensitivity to sulfonylureas, whereas SUR2A-based channels are distinguished from SUR2B channels by their differential sensitivity to diazoxide. Mutations that result in the loss of KATP channels in pancreatic beta-cells have been identified in SUR1 and KIR6.2. These mutations lead to familial hyperinsulinism. Understanding the mutations in SUR and KIR6.X is allowing insight into how these channels respond to nucleotides, sulfonylureas, and potassium channel openers, KCOs.

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Human alpha-endosulfine, a possible regulator of sulfonylurea-sensitive KATP channel: molecular cloning, expression and biological properties.

F Gribble, A Virsolvy, K Peyrollier … (1998)

Sulfonylureas are a class of drugs commonly used in the management of non-insulin-dependent diabetes mellitus. Their therapeutic action results primarily from their ability to inhibit ATP-sensitive potassium (KATP) channels in the plasma membrane of pancreatic beta cells and thereby stimulate insulin release. A key question is whether an endogenous ligand for the KATP channel exists that is able to mimic the inhibitory effects of sulfonylureas. We describe here the cloning of the cDNA encoding human alpha-endosulfine, a 13-kDa peptide that is a putative candidate for such a role. alpha-Endosulfine is expressed in a wide range of tissues including muscle, brain, and endocrine tissues. The recombinant protein displaces binding of the sulfonylurea [3H]glibenclamide to beta cell membranes, inhibits cloned KATP channel currents, and stimulates insulin secretion. We propose that endosulfine is an endogenous regulator of the KATP channel, which has a key role in the control of insulin release and, more generally, couples cell metabolism to electrical activity.

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Effects of oral antihyperglycemic agents on extracellular matrix synthesis by mesangial cells.

Claudia Cortes, Albert J Yee, K. Asano … (1998)

Increased expression of the glucose transporter GLUT1 in mesangial cells (MCs) markedly stimulates glucose transport and the formation of extracellular matrix (ECM), even when ambient glucose concentrations are low. Certain antihyperglycemic agents cause GLUT1 overexpression and increase glucose transport in various tissues. However, their effects on the kidney are unknown. Because diabetic glomerulosclerosis is characterized by the accumulation of mesangial matrix, was studied the effects of antihyperglycemic agents on matrix metabolism in MCs cultured either in 8 or 20 mM glucose. Membrane-associated GLUT1 was measured by immunoblotting. The initial rate of glucose transport was determined according to the 2-deoxy-D[14C(U)]glucose uptake. Collagen metabolism was studied by metabolic radiolabeling with [14C]-proline. Fibronectin in the medium was measured by ELISA. GLUT1 mRNA was estimated by Northern analysis. The sulfonylurea tolazamide increased GLUT1 protein expression by 107 and 69% in 8 and 20 mM glucose-grown cells, respectively. However, GLUT1 mRNA levels remained unchanged. Transporter-dependent deoxyglucose uptake was increased by tolazamide up to 184% in a dose-dependent fashion and was evident at both glucose concentrations after three or five days of exposure to the drug. Tolazamide significantly stimulated transforming growth factor-beta 1 (TGF-beta 1) secretion and the total synthesis of collagen and collagen and fibronectin accumulation in the medium of MCs maintained in high or low glucose concentrations. The biguanide metformin did not alter GLUT1 expression, glucose transport, fibronectin formation, or collagen metabolism, except at high concentrations. Tolazamide markedly enhances ECM synthesis and accumulation in MCs probably by stimulating GLUT1 expression, glucose transport and TGF-beta 1 secretion, irrespective of the ambient glucose concentration. This effect was dose-dependent and minimally inducible by metformin.

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Author and article information

Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2002

Publication date (Print): 2002

Publication date (Electronic): 09 January 2002

Volume: 10

Issue: 1

Pages: 1-6

Affiliations

Department of Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Mich., USA

Article

Publisher ID: 49892 Other ID: Exp Nephrol 2002;10:1–6

DOI: 10.1159/000049892

SO-VID: 62eaacdb-1729-4421-b37b-89bbd0ac4dd0

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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.

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A New Mesangial Triumvirate: Sulfonylureas, Their Receptors and Endosulfines

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Abstract

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Karger: Nephrology

Most cited references 4

A view of sur/KIR6.X, KATP channels.

Human alpha-endosulfine, a possible regulator of sulfonylurea-sensitive KATP channel: molecular cloning, expression and biological properties.

Effects of oral antihyperglycemic agents on extracellular matrix synthesis by mesangial cells.

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