Transglutaminase transcription and antigen translocation in experimental renal scarring

Timothy S. Johnson, N. Skill, A. Meguid El Nahas, Simon D. Oldroyd, Graham L. Thomas, Julie A. Douthwaite, John L. Haylor, Martin Griffin

Research output: Contribution to journalArticle

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Abstract

It was recently demonstrated that renal tissue transglutaminase (tTg) protein and its catalytic product the ε(γ-glutamyl) lysine protein cross- link are significantly increased in the subtotal (5/6) nephrectomy model (SNx) of renal fibrosis in rats. It was proposed that the enzyme had two important physiologic functions in disease development; one of stabilizing the increased extracellular matrix (ECM) by protein cross-linking, the other in a novel form of tubular cell death. This study, using the same rat SNx model, demonstrates first by Northern blotting that expression of tTg mRNA when compared with controls is increased by day 15 (+70% increase, P <0.05), then rises steadily, peaking at day 90 (+391%, P <0.01), and remains elevated at 120 d (+205%, P <0.05) when compared with controls, in situ hybridization histochemistry demonstrated that the tubular cells were the major site of the additional tTg synthesis. Immunohistochemistry on cryostat sections revealed a sixfold increase (P <0.001) in ECM-bound tTg antigen at 90-d post-SNx, whereas in situ transglutaminase activity demonstrated by the incorporation of fluorescein cadaverine into cryostat sections indicated a 750% increase (P <0.001) on day 90 in SNx animals. This increased activity was extracellular and predominantly found in the peritubular region. These results indicate that increased tTg gene transcription by tubular cells underlies the major changes in renal tTg protein reported previously in SNx rats, and that the presence of the ε(γ-glutamyl) lysine cross-links iri the extracellular environment is the result of the extracellular action of tTg. These changes may be in response to tubular cell injury during the scarring process and are likely to contribute to the progressive expansion of the ECM in renal fibrosis.

Original languageEnglish (US)
Pages (from-to)2145-2157
Number of pages13
JournalJournal of the American Society of Nephrology
Volume10
Issue number10
StatePublished - Oct 1999
Externally publishedYes

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Transglutaminases
Cicatrix
Kidney
Antigens
Lysine
Extracellular Matrix
Fibrosis
Cadaverine
Extracellular Matrix Proteins
transglutaminase 2
Nephrectomy
Fluorescein
Northern Blotting
In Situ Hybridization
Proteins
Cell Death
Immunohistochemistry
Messenger RNA
Wounds and Injuries
Enzymes

ASJC Scopus subject areas

  • Nephrology

Cite this

Johnson, T. S., Skill, N., El Nahas, A. M., Oldroyd, S. D., Thomas, G. L., Douthwaite, J. A., ... Griffin, M. (1999). Transglutaminase transcription and antigen translocation in experimental renal scarring. Journal of the American Society of Nephrology, 10(10), 2145-2157.

Transglutaminase transcription and antigen translocation in experimental renal scarring. / Johnson, Timothy S.; Skill, N.; El Nahas, A. Meguid; Oldroyd, Simon D.; Thomas, Graham L.; Douthwaite, Julie A.; Haylor, John L.; Griffin, Martin.

In: Journal of the American Society of Nephrology, Vol. 10, No. 10, 10.1999, p. 2145-2157.

Research output: Contribution to journalArticle

Johnson, TS, Skill, N, El Nahas, AM, Oldroyd, SD, Thomas, GL, Douthwaite, JA, Haylor, JL & Griffin, M 1999, 'Transglutaminase transcription and antigen translocation in experimental renal scarring', Journal of the American Society of Nephrology, vol. 10, no. 10, pp. 2145-2157.
Johnson TS, Skill N, El Nahas AM, Oldroyd SD, Thomas GL, Douthwaite JA et al. Transglutaminase transcription and antigen translocation in experimental renal scarring. Journal of the American Society of Nephrology. 1999 Oct;10(10):2145-2157.
Johnson, Timothy S. ; Skill, N. ; El Nahas, A. Meguid ; Oldroyd, Simon D. ; Thomas, Graham L. ; Douthwaite, Julie A. ; Haylor, John L. ; Griffin, Martin. / Transglutaminase transcription and antigen translocation in experimental renal scarring. In: Journal of the American Society of Nephrology. 1999 ; Vol. 10, No. 10. pp. 2145-2157.
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