Smad7 as a therapeutic agent for chronic kidney diseases

被引:102
作者
Lan, Hui Yao [1 ]
机构
[1] Univ Hong Kong, Li Ka Shing Fac Med, Dept Med, Pokfulam, Hong Kong, Peoples R China
来源
FRONTIERS IN BIOSCIENCE-LANDMARK | 2008年 / 13卷
关键词
TGF-beta; Smad signaling; Smad7; chronic kidney disease; fibrosis; inflammation; gene therapy; review;
D O I
10.2741/3057
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Increasing evidence shows that transforming growth factor-beta TGF-beta 1 (TGF-beta 1) is upregulated and plays a diverse role in renal fibrosis by stimulating extracellular matrix (ECM) production, while inhibiting renal inflammation. Recent studies have identified that TGF-beta 1, once activated, signals through its downstream signaling pathway to exert its biological effects. It is now well accepted that TGF-beta regulates fibrosis positively by receptor-associated Smads including Smad2 and Smad3, but negatively by an inhibitory Smad, called Smad7. We and other investigators have shown that gene transfer of Smad7 is able to inhibit renal fibrosis in a number of experimental models of chronic kidney diseases, including obstructive nephropathy, remnant kidney disease, and autoimmune crescentic glomerulonephritis. Blockade of Smad2/3 activation is a major mechanism by which overexpression of Smad7 inhibits renal scarring. Furthermore, our recent findings also demonstrate that Smad7 plays a critical role in anti-inflammation in chronic kidney diseases by blocking the NF.kappa B-dependent inflammatory pathway. Thus, Smad7 has a unique role in both anti-renal fibrosis and inflammation. These findings also indicate that targeting the TGF-beta/Smad signaling pathway by overexpressing Smad7 may provide a novel, specific, and effective therapy for chronic kidney diseases.
引用
收藏
页码:4984 / 4992
页数:9
相关论文
共 61 条
[1]   Induction of inhibitory Smad6 and Smad7 mRNA by TGF-β family members [J].
Afrakhte, M ;
Morén, A ;
Jossan, S ;
Itoh, S ;
Westermark, B ;
Heldin, CH ;
Heldin, NE ;
ten Dijke, P .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 249 (02) :505-511
[2]   TGF-β1 inhibits NF-κB activity through induction of IκB-α expression in human salivary gland cells:: A possible mechanism of growth suppression by TGF-1β [J].
Azuma, M ;
Motegi, K ;
Aota, K ;
Yamashita, T ;
Yoshida, H ;
Sato, M .
EXPERIMENTAL CELL RESEARCH, 1999, 250 (01) :213-222
[3]  
Bitzer M, 2000, GENE DEV, V14, P187
[4]   Science, medicine, and the future - Microbubble contrast agents: a new era in ultrasound [J].
Blomley, MJK ;
Cooke, JC ;
Unger, EC ;
Monaghan, MJ ;
Cosgrove, DO .
BMJ-BRITISH MEDICAL JOURNAL, 2001, 322 (7296) :1222-1225
[5]   Smad3 null mice develop airspace enlargement and are resistant to TGF-β-mediated pulmonary fibrosis [J].
Bonniaud, P ;
Kolb, M ;
Galt, T ;
Robertson, J ;
Robbins, C ;
Stampfli, M ;
Lavery, C ;
Margetts, PJ ;
Roberts, AB ;
Gauldie, J .
JOURNAL OF IMMUNOLOGY, 2004, 173 (03) :2099-2108
[6]   Evidence that TGF-β should he a therapeutic target in diabetic nephropathy [J].
Border, WA ;
Noble, NA .
KIDNEY INTERNATIONAL, 1998, 54 (04) :1390-1391
[7]   TGF-β in renal injury and disease [J].
Bottinger, Erwin P. .
SEMINARS IN NEPHROLOGY, 2007, 27 (03) :309-320
[8]  
Chen RH, 2002, J AM SOC NEPHROL, V13, DOI 10.1681/ASN.V134887
[9]   Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model [J].
Chernajovsky, Y ;
Adams, G ;
Triantaphyllopoulos, K ;
Ledda, MF ;
Podhajcer, OL .
GENE THERAPY, 1997, 4 (06) :553-559
[10]   Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation [J].
Ebisawa, T ;
Fukuchi, M ;
Murakami, G ;
Chiba, T ;
Tanaka, K ;
Imamura, T ;
Miyazono, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (16) :12477-12480