Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: a potential mechanism of tissue scarring

Marie Fisher, Richard A. Jones, Linghong Huang, John L. Haylor, Meguid El Nahas, Martin Griffin, Timothy S. Johnson

Research output: Contribution to journalArticle

Abstract

The up-regulation and trafficking of tissue transglutaminase (TG2) by tubular epithelial cells (TEC) has been implicated in the development of kidney scarring. TG2 catalyses the crosslinking of proteins via the formation of highly stable e(?-glutamyl) lysine bonds. We have proposed that TG2 may contribute to kidney scarring by accelerating extracellular matrix (ECM) deposition and by stabilising the ECM against proteolytic decay. To investigate this, we have studied ECM metabolism in Opossum kidney (OK) TEC induced to over-express TG2 by stable transfection and in tubular cells isolated from TG2 knockout mice. Increasing the expression of TG2 led to increased extracellular TG2 activity (p < 0.05), elevated e(?-glutamyl) lysine crosslinking in the ECM and higher levels of ECM collagen per cell by 3H-proline labelling. Immunofluorescence demonstrated that this was attributable to increased collagen III and IV levels. Higher TG2 levels were associated with an accelerated collagen deposition rate and a reduced ECM breakdown by matrix metalloproteinases (MMPs). In contrast, a lack of TG2 was associated with reduced e(?-glutamyl) lysine crosslinking in the ECM, causing reduced ECM collagen levels and lower ECM per cell. We report that TG2 contributes to ECM accumulation primarily by accelerating collagen deposition, but also by altering the susceptibility of the tubular ECM to decay. These findings support a role for TG2 in the expansion of the ECM associated with kidney scarring.
LanguageEnglish
Pages20-31
Number of pages12
JournalMatrix Biology
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2009

Fingerprint

Cicatrix
Extracellular Matrix
Epithelial Cells
Collagen
Lysine
Kidney
transglutaminase 2
Opossums
Matrix Metalloproteinases
Proline
Knockout Mice
Fluorescent Antibody Technique
Transfection
Up-Regulation

Keywords

  • transglutaminase
  • collagen
  • scarring
  • metalloproteinases
  • extracellular matrix

Cite this

Fisher, Marie ; Jones, Richard A. ; Huang, Linghong ; Haylor, John L. ; El Nahas, Meguid ; Griffin, Martin ; Johnson, Timothy S. / Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: a potential mechanism of tissue scarring. In: Matrix Biology. 2009 ; Vol. 28, No. 1. pp. 20-31.
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Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: a potential mechanism of tissue scarring. / Fisher, Marie; Jones, Richard A.; Huang, Linghong; Haylor, John L.; El Nahas, Meguid; Griffin, Martin; Johnson, Timothy S.

In: Matrix Biology, Vol. 28, No. 1, 01.2009, p. 20-31.

Research output: Contribution to journalArticle

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