Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells

被引：18
作者：
O'Donovan, Helen C. [1 ]
Hickey, Fionnuala [2 ]
Brazil, Derek P. [3 ]
Kavanagh, David H. [4 ]
Oliver, Noelynn [5 ]
Martin, Finian [1 ]
Godson, Catherine [2 ]
Crean, John [1 ]
机构：
[1] Univ Coll Dublin, Sch Biomol & Biomed Sci, Dublin 4, Ireland
[2] Univ Coll Dublin, Conway Inst, Univ Coll Dublin Sch Med & Med Sci, Dublin 4, Ireland
[3] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland
[4] Queens Univ Belfast, Ctr Publ Hlth, Nephrol Res Grp, Belfast, Antrim, North Ireland
[5] FibroGen, San Francisco, CA 94158 USA
来源：
BIOCHEMICAL JOURNAL | 2012年 / 441卷
基金：
爱尔兰科学基金会;
关键词：
connective tissue growth factor (CTGF); p42/44 MAPK (mitogen-activated protein kinase); signalling cross-talk; Smad signalling; transforming growth factor-beta (TGF-beta); transforming growth factor-beta 1 receptor; ERK MAP KINASE; TGF-BETA; DIABETIC-NEPHROPATHY; CROSS-TALK; EXPRESSION; PHOSPHORYLATION; CTGF; RECEPTOR; PROLIFERATION; RESPONSES;
D O I：
10.1042/BJ20110910
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：
The critical involvement of TGF-beta 1 (transforming growth factor-beta 1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-beta 1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-beta 1 and its physiological significance. CTGF was determined to bind directly to the T beta RIII (TGF-beta type III receptor) and antagonize TGF-beta 1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-beta 1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-beta 1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-beta 1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF Knockdown of T beta RIII restored TGF-beta 1-mediated Smad signalling and cell contractility, suggesting that T beta RIII is key for CTGF-mediated regulation of TGF-beta 1. Comparison of gene expression profiles from CTGF/TGF-beta 1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-beta 1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.
引用
收藏
页码：499 / 510
页数：12
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