Interplay between transglutaminases and heparan sulphate in progressive renal scarring

Burhan, I, Furini, G, Lortat-Jacob, H, Atobatele, AG, Scarpellini, A, Schroeder, N, Atkinson, J, Maamra, M, Nutter, FH, Watson, Philip, Vinciguerra, M, Johnson, TS and Verderio, EAM ORCID: 0000-0001-9153-8997, 2016. Interplay between transglutaminases and heparan sulphate in progressive renal scarring. Scientific Reports, 6, p. 31343. ISSN 2045-2322

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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.

Item Type: Journal article
Publication Title: Scientific Reports
Creators: 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. and Verderio, E.A.M.
Publisher: Nature Publishing Group
Date: 3 October 2016
Volume: 6
ISSN: 2045-2322
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 07 Oct 2016 10:02
Last Modified: 09 Jun 2017 14:07

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