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J. Biol. Chem., Vol. 279, Issue 46, 47754-47762, November 12, 2004

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Inhibition of Transglutaminase Activity Reduces Extracellular Matrix Accumulation Induced by High Glucose Levels in Proximal Tubular Epithelial Cells^*

Nicholas J. Skill¶, Timothy S. Johnson¶, Ian G. C. Coutts, Robert E. Saint, Marie Fisher, Linghong Huang, A. Meguid El Nahas, Russell J. Collighan, and Martin Griffin||

From the School of Science, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS United Kingdom and the Sheffield Kidney Institute, Northern General Hospital, Sheffield S5 7AU, United Kingdom

Diabetic nephropathy affects 30–40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product (-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mM glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM (-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated (-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor 1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor 1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.

Received for publication, March 10, 2004 , and in revised form, August 20, 2004.

^* This work was supported by the Wellcome Trust (Grant 066379), the Engineering and Physical Sciences Research Council (Grant GR/S21755/01), the Northern General Hospital Research Committee (Grant 180 to N. J. S.), and the National Kidney Research Fund (SF/2/2000 to T. S. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Tel.: 44-(0)115-848-6670; Fax: 44-(0)115-848-6636; E-mail: martin.griffin{at}ntu.ac.uk.

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