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

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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

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

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Transglutaminases
Chronic Renal Insufficiency
Fibrosis
Extracellular Matrix
Collagen
Kidney
Transforming Growth Factors
Nephrectomy
Lung
Skin
Liver
Enzymes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Nephrology

Cite this

Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease. / Johnson, Tim S.; Fisher, Marie; Haylor, John L.; Hau, Zoe; Skill, N.; Jones, Richard; Saint, Robert; Coutts, Ian; Vickers, Melissa E.; El Nahas, A. Meguid; Griffin, Martin.

In: Journal of the American Society of Nephrology, Vol. 18, No. 12, 12.2007, p. 3078-3088.

Research output: Contribution to journalArticle

Johnson, TS, Fisher, M, Haylor, JL, Hau, Z, Skill, N, Jones, R, Saint, R, Coutts, I, Vickers, ME, El Nahas, AM & Griffin, M 2007, 'Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease', Journal of the American Society of Nephrology, vol. 18, no. 12, pp. 3078-3088. https://doi.org/10.1681/ASN.2006070690
Johnson, Tim S. ; Fisher, Marie ; Haylor, John L. ; Hau, Zoe ; Skill, N. ; Jones, Richard ; Saint, Robert ; Coutts, Ian ; Vickers, Melissa E. ; El Nahas, A. Meguid ; Griffin, Martin. / Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease. In: Journal of the American Society of Nephrology. 2007 ; Vol. 18, No. 12. pp. 3078-3088.
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