Transglutaminase inhibition ameliorates experimental diabetic nephropathy.
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.
Huang
Linghong
L
Academic Nephrology Unit, Sheffield Kidney Institute, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK.
Haylor
John L
JL
Hau
Zoe
Z
Jones
Richard A
RA
Vickers
Melissa E
ME
Wagner
Bart
B
Griffin
Martin
M
Saint
Robert E
RE
Coutts
Ian G C
IG
El Nahas
A Meguid
AM
Johnson
Timothy S
TS
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects; D005920:Glomerular Mesangium / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D011503:Transglutaminases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D013311:Streptozocin; D003094:Collagen; D011503:Transglutaminases