1. ¹Academic Nephrology Unit, Sheffield Kidney Institute, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK
2. ²Biomedical Sciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
3. ³Department of Histology, Northern General Hospital, Sheffied, UK
4. ⁴School of Health and Life Sciences, Aston University, Birmingham, UK

Correspondence: Timothy S. Johnson, Academic Nephrology Unit, Sheffield Kidney Institute, Room GU24, School of Medicine and Biomedical Sciences, The University of Sheffield, Royal Hallamshire Hospital, Beech Hill Road, Sheffield S10 2RZ, UK. E-mail: t.johnson@sheffield.ac.uk

^*The study is dedicated to the memory of Dr Richard Jones who died tragically while completing this study.

Received 14 August 2008; Revised 30 April 2009; Accepted 5 May 2009; Published online 24 June 2009.

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 -(-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.