title: Syndecan-4 knockout leads to reduced extracellular transglutaminase-2 and protects against tubulointerstitial fibrosis.
abstract: Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. The interaction of TG2 with the heparan sulfate proteoglycan syndecan-4 (Sdc4) regulates the cell surface trafficking, localization, and activity of TG2 in vitro but remains unstudied in vivo. We tested the hypothesis that Sdc4 is required for cell surface targeting of TG2 and the development of kidney fibrosis in CKD. Wild-type and Sdc4-null mice were subjected to unilateral ureteric obstruction and aristolochic acid nephropathy (AAN) as experimental models of kidney fibrosis. Analysis of renal scarring by Masson trichrome staining, kidney hydroxyproline levels, and collagen immunofluorescence demonstrated progressive fibrosis associated with increases in extracellular TG2 and TG activity in the tubulointerstitium in both models. Knockout of Sdc-4 reduced these effects and prevented AAN-induced increases in total and active TGF-β1. In wild-type mice subjected to AAN, extracellular TG2 colocalized with Sdc4 in the tubular interstitium and basement membrane, where TG2 also colocalized with heparan sulfate chains. Heparitinase I, which selectively cleaves heparan sulfate, completely abolished extracellular TG2 in normal and diseased kidney sections. In conclusion, the lack of Sdc4 heparan sulfate chains in the kidneys of Sdc4-null mice abrogates injury-induced externalization of TG2, thereby preventing profibrotic crosslinking of extracellular matrix and recruitment of large latent TGF-β1. This finding suggests that targeting the TG2-Sdc4 interaction may provide a specific interventional strategy for the treatment of CKD.
authors.affiliation: School of Science and Technology, Biomedical, Life and Health Research Centre, Nottingham Trent University, Nottingham, United Kingdom; and.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scarpellini
authors.affiliation: Academic Nephrology Unit, Sheffield Kidney Institute, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Linghong
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Science and Technology, Biomedical, Life and Health Research Centre, Nottingham Trent University, Nottingham, United Kingdom; and.
authors.forename: Izhar
authors.initials: I
authors.lastname: Burhan
authors.affiliation: School of Science and Technology, Biomedical, Life and Health Research Centre, Nottingham Trent University, Nottingham, United Kingdom; and.
authors.forename: Nina
authors.initials: N
authors.lastname: Schroeder
authors.affiliation: School of Science and Technology, Biomedical, Life and Health Research Centre, Nottingham Trent University, Nottingham, United Kingdom; and.
authors.forename: Muriel
authors.initials: M
authors.lastname: Funck
authors.affiliation: Academic Nephrology Unit, Sheffield Kidney Institute, University of Sheffield, Sheffield, United Kingdom elisabetta.verderio-edwards@ntu.ac.uk t.johnson@sheffield.ac.uk.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Johnson
authors.affiliation: School of Science and Technology, Biomedical, Life and Health Research Centre, Nottingham Trent University, Nottingham, United Kingdom; and elisabetta.verderio-edwards@ntu.ac.uk t.johnson@sheffield.ac.uk.
authors.forename: Elisabetta A M
authors.initials: EA
authors.lastname: Verderio
mesh_terms: D000818:Animals; D034341:Aristolochic Acids; D005355:Fibrosis; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009400:Nephrosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D053671:Syndecan-4 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D014605:Uveitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D034341:Aristolochic Acids; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C000228:aristolochic acid I; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins