1. Interplay between transglutaminases and heparan sulphate in progressive renal scarring
- Author
-
Hugues Lortat-Jacob, Philip F. Watson, Giulia Furini, Faith Nutter, John M. Atkinson, Adeola G. Atobatele, M. Maamra, Nina Schroeder, Manlio Vinciguerra, Alessandra Scarpellini, Elisabetta A.M. Verderio, Timothy S. Johnson, Izhar Burhan, Nottingham Trent University, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Burhan I, Furini G, Lortat-Jacob H, Atobatele A G, Scarpellini A, Schroeder N, Atkinson J, Maamra M, Nutter F H, Watson P, Vinciguerra M, Johnson T S, Verderio Edwards E, Institut de biologie structurale [1992-2019] (IBS - UMR 5075 [1992-2019]), University of Sheffield [Sheffield], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,none ,Tissue transglutaminase ,Matrix (biology) ,Kidney Function Tests ,Bioinformatics ,Article ,Cell Line ,Transforming Growth Factor beta1 ,Extracellular matrix ,Mice ,03 medical and health sciences ,Glomerulonephritis ,GTP-Binding Proteins ,Extracellular ,medicine ,Animals ,Protein Glutamine gamma Glutamyltransferase 2 ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Binding site ,ComputingMilieux_MISCELLANEOUS ,Kidney ,Binding Sites ,Transglutaminases ,Multidisciplinary ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Heparin ,Rats ,Cell biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,NIH 3T3 Cells ,biology.protein ,Syndecan-4 ,Heparitin Sulfate ,Homeostasis ,medicine.drug - Abstract
Transglutaminase-2 (TG2) is a new anti-fibrotic target for chronic kidney disease, for its role in altering the extracellular homeostatic balance leading to excessive build-up of matrix in kidney. However, there is no confirmation that TG2 is the only transglutaminase involved, neither there are strategies to control its action specifically over that of the conserved family-members. In this study, we have profiled transglutaminase isozymes in the rat subtotal nephrectomy (SNx) model of progressive renal scarring. All transglutaminases increased post-SNx peaking at loss of renal function but TG2 was the predominant enzyme. Upon SNx, extracellular TG2 deposited in the tubulointerstitium and peri-glomerulus via binding to heparan sulphate (HS) chains of proteoglycans and co-associated with syndecan-4. Extracellular TG2 was sufficient to activate transforming growth factor-β1 in tubular epithelial cells and this process occurred in a HS-dependent way, in keeping with TG2-affinity for HS. Analysis of heparin binding of the main transglutaminases revealed that although the interaction between TG1 and HS is strong, the conformational heparin binding site of TG2 is not conserved, suggesting that TG2 has a unique interaction with HS within the family. Our data provides a rationale for a novel anti-fibrotic strategy specifically targeting the conformation-dependent TG2-epitope interacting with HS.
- Published
- 2016
- Full Text
- View/download PDF