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
[41]   Smad3:: A key player in pathogenetic mechanisms dependent on TGF-β [J].
Roberts, AB ;
Russo, A ;
Felici, A ;
Flanders, KC .
TISSUE REMODELING, 2003, 995 :1-10
[42]   Molecular and cell biology of TGF-β [J].
Roberts, AB .
MINERAL AND ELECTROLYTE METABOLISM, 1998, 24 (2-3) :111-119
[43]   Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-β-independent mechanism [J].
Rodríguez-Vita, J ;
Sánchez-López, E ;
Esteban, V ;
Rupérez, M ;
Egido, J ;
Ruiz-Ortega, M .
CIRCULATION, 2005, 111 (19) :2509-2517
[44]   HEPATIC EXPRESSION OF MATURE TRANSFORMING GROWTH-FACTOR-BETA-1 IN TRANSGENIC MICE RESULTS IN MULTIPLE TISSUE LESIONS [J].
SANDERSON, N ;
FACTOR, V ;
NAGY, P ;
KOPP, J ;
KONDAIAH, P ;
WAKEFIELD, L ;
ROBERTS, AB ;
SPORN, MB ;
THORGEIRSSON, SS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (07) :2572-2576
[45]   Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction [J].
Sato, M ;
Muragaki, Y ;
Saika, S ;
Roberts, AB ;
Ooshima, A .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (10) :1486-1494
[46]  
Schiffer M, 2001, J CLIN INVEST, V108, P807, DOI 10.1172/JCI12367
[47]  
Schnaper HW, 2002, J AM SOC NEPHROL, V13, DOI 10.1681/ASN.V1341126
[48]   The balance between acetylation and deacetylation controls Smad7 stability [J].
Simonsson, M ;
Heldin, CH ;
Ericsson, J ;
Grönroos, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (23) :21797-21803
[49]   The balance between CD45RChigh and CD45RClow CD4 T cells in rats is intrinsic to bone marrow-derived cells and is genetically controlled [J].
Subra, JF ;
Cautain, B ;
Xystrakis, E ;
Mas, M ;
Lagrange, D ;
van der Heijden, H ;
van de Gaar, MJ ;
Druet, P ;
Fournié, GJ ;
Saoudi, A ;
Damoiseaux, J .
JOURNAL OF IMMUNOLOGY, 2001, 166 (05) :2944-2952
[50]   Downregulation of SnoN expression in obstructive nephropathy is mediated by an enhanced ubiquitin-dependent degradation [J].
Tan, Ruoyun ;
Zhang, Jinglan ;
Tan, Xiaoyue ;
Zhang, Xianghong ;
Yang, Junwei ;
Liu, Youhua .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (10) :2781-2791