Transglutaminase inhibition ameliorates experimental diabetic nephropathy

Linghong Huang, John L. Haylor, Zoe Hau, Richard A. Jones, Melissa E. Vickers, Bart Wagner, Martin Griffin, Robert E. Saint, Ian G.C. Coutts, A. Meguid El Nahas, Timothy S. Johnson

Research output: Contribution to journalArticle

Abstract

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.
LanguageEnglish
Pages383-394
Number of pages12
JournalKidney international
Volume76
Issue number4
DOIs
Publication statusPublished - Aug 2009

Fingerprint

Transglutaminases
Diabetic Nephropathies
Myofibroblasts
Cicatrix
Extracellular Matrix
Collagen
Albuminuria
Streptozocin
Basement Membrane
Chronic Kidney Failure
Creatinine
Homeostasis
Kidney
Serum
Proteins
transglutaminase 2

Keywords

  • diabetic nephropathy
  • extracellular matrix accumulation
  • renal scarring
  • end-stage renal diseas
  • transglutaminase type 2
  • protein crosslink product
  • ε-(γ-glutamyl)lysine
  • extracellular matrix homeostasis
  • basement membrane thickening
  • mesangium
  • interstitium
  • transglutaminase inhibition
  • chronic experimental diabetic nephropathy
  • treatment period
  • inhibitor NTU281
  • uninephrectomized streptozotocin-induced diabete
  • experimental diabetic nephropathy
  • clinical application

Cite this

Huang, L., Haylor, J. L., Hau, Z., Jones, R. A., Vickers, M. E., Wagner, B., ... Johnson, T. S. (2009). Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney international, 76(4), 383-394. https://doi.org/10.1038/ki.2009.230
Huang, Linghong ; Haylor, John L. ; Hau, Zoe ; Jones, Richard A. ; Vickers, Melissa E. ; Wagner, Bart ; Griffin, Martin ; Saint, Robert E. ; Coutts, Ian G.C. ; El Nahas, A. Meguid ; Johnson, Timothy S. / Transglutaminase inhibition ameliorates experimental diabetic nephropathy. In: Kidney international. 2009 ; Vol. 76, No. 4. pp. 383-394.
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Huang, L, Haylor, JL, Hau, Z, Jones, RA, Vickers, ME, Wagner, B, Griffin, M, Saint, RE, Coutts, IGC, El Nahas, AM & Johnson, TS 2009, 'Transglutaminase inhibition ameliorates experimental diabetic nephropathy' Kidney international, vol. 76, no. 4, pp. 383-394. https://doi.org/10.1038/ki.2009.230

Transglutaminase inhibition ameliorates experimental diabetic nephropathy. / Huang, Linghong; Haylor, John L.; Hau, Zoe; Jones, Richard A.; Vickers, Melissa E.; Wagner, Bart; Griffin, Martin; Saint, Robert E.; Coutts, Ian G.C.; El Nahas, A. Meguid; Johnson, Timothy S.

In: Kidney international, Vol. 76, No. 4, 08.2009, p. 383-394.

Research output: Contribution to journalArticle

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Huang L, Haylor JL, Hau Z, Jones RA, Vickers ME, Wagner B et al. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney international. 2009 Aug;76(4):383-394. https://doi.org/10.1038/ki.2009.230