机构：[1]Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.[2]Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.中山大学附属第一医院[3]Division of Nephrology, Department of Internal Medicine, West China Hospital of Sichuan University, Chengdu, P.R. China.四川大学华西医院[4]Florida State University College of Medicine, Tallahassee, Florida, USA.[5]Centre for Cancer Research, Hadson Institute of Medical Research, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.[6]Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.中山大学附属第二医院[7]Department of Nephrology, Department of Medicine, Monash Health and Monash University, Clayton, Victoria, Australia.
Transforming growth factor-β1 (TGF-β1)/Smad signaling has a central role in the pathogenesis of renal fibrosis. Smad3 and Smad4 are pro-fibrotic, while Smad2 is anti-fibrotic. However, these Smads form heterogeneous complexes, the functions of which are poorly understood. Here we studied Smad complex function in renal fibrosis using the mouse model of unilateral ureteric obstruction. Mice heterozygous for Smad3/4 (Smad3/4+/-) exhibited substantial protection from renal fibrosis through day 7 of obstruction, whereas Smad2/3+/- and Smad2/4+/- mice showed only modest protection. Formation of Smad3/Smad4/CDK9 complexes was an early event following obstruction in wild-type mice, which involved nuclear phosphorylation of the linker regions of Smad3. Significantly, Smad3 or Smad4 deficiency decreased the formation of Smad4/CDK9 or Smad3/CDK9 complex, Smad3 linker phosphorylation, and fibrosis but at different degrees. In vitro, TGF-β1 stimulation of collagen I promoter activity involved formation of Smad3/Smad4/CDK9 complexes, and overexpression of each component gave additive increases in collagen promoter activity. Co-administration of a CDK9 inhibitor and Smad3-specific inhibition achieved better protection from TGF-β1-induced fibrotic response in vitro and renal interstitial fibrosis in vivo. Thus formation of Smad3/Smad4/CDK9 complex drives renal fibrosis during ureteral obstruction. Formation of this complex represents a novel target for antifibrotic therapies.
基金：
Monash University Accelerating
Program and the National Health and Medical Research Council
(NHMRC) of Australia (APP1057581).
第一作者机构：[1]Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
通讯作者：
通讯机构：[1]Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.[2]Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.[*1]Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, P.R. China[*2]Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
推荐引用方式(GB/T 7714)：
Qu Xinli,Jiang Mengjie,Sun Yu Bo Yang,et al.The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction.[J].KIDNEY INTERNATIONAL.2015,88(6):1323-1335.doi:10.1038/ki.2015.235.
APA：
Qu Xinli,Jiang Mengjie,Sun Yu Bo Yang,Jiang Xiaoyun,Fu Ping...&Li Jinhua.(2015).The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction..KIDNEY INTERNATIONAL,88,(6)
MLA：
Qu Xinli,et al."The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction.".KIDNEY INTERNATIONAL 88..6(2015):1323-1335
医学