Interplay between transglutaminases and heparan sulphate in progressive renal scarring.
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.
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Izhar
I
Burhan
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Giulia
G
Furini
Institut de Biologie Structurale, UMR 5075, Univ. Grenoble Alpes, CNRS, CEA, Grenoble, F-38027, France.
Hugues
H
Lortat-Jacob
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Adeola G
AG
Atobatele
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Alessandra
A
Scarpellini
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Nina
N
Schroeder
University of Sheffield, Academic Nephrology Unit, Medical School, Sheffield, S10 2RZ, United Kingdom.
John
J
Atkinson
University of Sheffield, Academic Nephrology Unit, Medical School, Sheffield, S10 2RZ, United Kingdom.
Mabrouka
M
Maamra
University of Sheffield, Academic Nephrology Unit, Medical School, Sheffield, S10 2RZ, United Kingdom.
Faith H
FH
Nutter
University of Sheffield, Academic Nephrology Unit, Medical School, Sheffield, S10 2RZ, United Kingdom.
Philip
P
Watson
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Manlio
M
Vinciguerra
University of Sheffield, Academic Nephrology Unit, Medical School, Sheffield, S10 2RZ, United Kingdom.
Timothy S
TS
Johnson
Nottingham Trent University, School of Science and Technology, Nottingham, NG11 8NS, United Kingdom.
Elisabetta A M
EA
Verderio
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000201:enzymology* / Q000503:physiopathology; D006497:Heparan Sulfate / Q000378:metabolism*; D007677:Kidney Function Tests; D051379:Mice; D041681:NIH 3T3 Cells; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D053671:Syndecan-4 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D011503:Transglutaminases / Q000737:chemistry / Q000378:metabolism*
D019204:GTP-Binding Proteins; D006497:Heparan Sulfate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D053671:Syndecan-4; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases; C508307:Sdc4 protein, rat; C508962:Tgfb1 protein, rat; C000717609:Tgm2 protein, rat; C105804:transglutaminase 1
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