Transglutaminase inhibition ameliorates experimental diabetic nephropathy

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Authors

  • 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 units

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.

Details

Original languageEnglish
Pages (from-to)383-394
Number of pages12
JournalKidney international
Volume76
Issue number4
DOIs
Publication statusPublished - Aug 2009

    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

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