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      A New Mesangial Triumvirate: Sulfonylureas, Their Receptors and Endosulfines

      Cardiorenal Medicine
      S. Karger AG
      Glucose transporter, Endosulfine, Mesangial cell, Sulfonylureas, Sulfonylurea receptor

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          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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          Most cited references4

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

          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.

            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.

              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.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                09 January 2002
                : 10
                : 1
                : 1-6
                Department of Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Mich., USA
                49892 Exp Nephrol 2002;10:1–6
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 31, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/49892
                Self URI (text/html): https://www.karger.com/Article/FullText/49892
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology

                Cardiovascular Medicine,Nephrology
                Mesangial cell,Glucose transporter,Sulfonylurea receptor,Endosulfine,Sulfonylureas


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