Interplay between transglutaminases and heparan sulphate in progressive renal scarring.

Izhar Burhan,Philip Watson,Adeola G Atobatele,Timothy S Johnson,Elisabetta A M Verderio,Nina Schroeder,Giulia Furini,Alessandra Scarpellini,Mabrouka Maamra,Hugues Lortat-Jacob,Manlio Vinciguerra,John Atkinson,Faith H Nutter

doi:10.1038/srep31343

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.

Highlights

Characterised with distinct genes, structures and physiological functions[3]
We have recently reported that knock-out (KO) of the heparan sulphate proteoglycans (HSPG) receptor syndecan-4 (Sdc4) ameliorates fibrosis in the murine unilateral ureteric obstruction (UUO) and aristolochic acid nephrotoxicity (AAN) models, and that this is connected with a lower level of extracellular TG2 protein and activity[27]
As the disease model progressed, all the TG family members rose steadily post-SNx, peaking at a time point of “advanced fibrosis”, which corresponds to severe renal scarring and follows the increase in extracellular matrix proteins (ECM) protein transcription[35], but TG2 was the highest expressed TG isozyme in both normal and diseased kidneys

Summary

Introduction

Characterised with distinct genes, structures and physiological functions[3]. Examples are factor XIIIa (FXIIIa), which stabilises fibrin during blood clotting, and TG1, which has a role in skin barrier formation. TG2 can be ascribed a role in changing renal ECM homeostasis[14], there is no confirmation that TG2 is the key player, neither there are strategies to control/prevent the fibrogenic action of extracellular TG2 in human disease New observations, both in vitro and in vivo, indicate that the biological role of TG2 may be modulated by its interaction with heparan sulphate proteoglycans (HSPG), key components of the tubular basement membrane[21]. Understanding whether TG2 is the main form implicated in fibrosis progression, whether its interaction with HS is unique and its significance in fibrosis development is a key goal for the development of new treatment strategies that target TG2 To address this need, we have measured the expression of TG family members in the 5/6th subtotal nephrectomy (SNx) model of renal scarring, which is regarded as a useful reproduction of chronic kidney scarring, comparable to that observed in human disease. This study broadens our understanding of the interplay between TG2 and HS/Sdc[4] in TGF-β1 activation and fibrosis

Methods

Results

Conclusion