Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease

Tim S. Johnson*, Marie Fisher, John L. Haylor, Zoe Hau, N. James Skill, Richard Jones, Robert Saint, Ian G.C. Coutts, Melissa E Vickers, A. Meguid El Nahas, Martin Griffin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Progressive tissue fibrosis is involved in debilitating diseases that affect organs including the lungs, liver, heart, skin, and kidneys. Recent evidence suggests that tissue transglutaminase, an enzyme that crosslinks proteins, may be involved in tissue fibrosis by crosslinking and stabilizing the extracellular matrix or by recruiting and activating the large latent transforming growth factor (TGF)-β1 complex. We treated rats that had undergone 5/6-nephrectomy with two different irreversible inhibitors of transglutaminase and found that both prevented a decline in kidney function and reduced the development of glomerulosclerosis and tubulointerstitial fibrosis by up to 77% and 92%, respectively. Treatment reduced the accumulation of collagen I and collagen III, with the primary mechanism of action being direct interference with the crosslinking of extracellular matrix rather than altered regulation of TGFβ1. We conclude that inhibition of transglutaminase offers a potential therapeutic option for chronic kidney disease and other conditions that result from tissue fibrosis. Copyright © 2007 by the American Society of Nephrology.

Original languageEnglish
Pages (from-to)3078-3088
Number of pages11
JournalJournal of the American Society of Nephrology
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2007

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