title: The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction.
abstract: 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.
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Xinli
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Yu Bo Yang
authors.initials: YB
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, West China Hospital of Sichuan University, Chengdu, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Florida State University College of Medicine, Tallahassee, Florida, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Centre for Cancer Research, Hadson Institute of Medical Research, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Lie
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Georgina
authors.initials: G
authors.lastname: Caruana
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Bertram
authors.affiliation: Department of Nephrology, Department of Medicine, Monash Health and Monash University, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.|Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Li