Transglutaminase inhibition ameliorates experimental diabetic nephropathy

被引:85
作者
Huang, Linghong
Haylor, John L.
Hau, Zoe
Jones, Richard A. [2 ]
Vickers, Melissa E.
Wagner, Bart [4 ]
Griffin, Martin [3 ]
Saint, Robert E. [2 ]
Coutts, Ian G. C. [2 ]
El Nahas, A. Meguid
Johnson, Timothy S. [1 ]
机构
[1] Univ Sheffield, Royal Hallamshire Hosp, Acad Nephrol Unit, Sheffield Kidney Inst,Sch Med & Biomed Sci, Sheffield S10 2RZ, S Yorkshire, England
[2] Nottingham Trent Univ, Sch Sci & Technol, Nottingham, England
[3] Aston Univ, Sch Life & Hlth Sci, Birmingham B4 7ET, W Midlands, England
[4] No Gen Hosp, Dept Histol, Sheffield S5 7AU, S Yorkshire, England
基金
英国惠康基金;
关键词
collagen; crosslink; diabetic nephropathy; extracellular matrix; renal scarring; transglutaminase; GROWTH-FACTOR-BETA; TISSUE TRANSGLUTAMINASE; CROSS-LINKING; TRANSFORMING GROWTH-FACTOR-BETA-1; MESENCHYMAL TRANSITION; DERMAL FIBROBLASTS; MYOFIBROBLASTS; COLLAGEN; ACTIVATION; PROGRESSION;
D O I
10.1038/ki.2009.230
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:383 / 394
页数:12
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