title: Characterization and role of SCAI during renal fibrosis and epithelial-to-mesenchymal transition.
abstract: During progressive tubulointerstitial fibrosis, renal tubular epithelial cells transform into α-smooth muscle actin (SMA)-expressing myofibroblasts via epithelial-to-mesenchymal transition (EMT). SMA expression is regulated by transforming growth factor (TGF)-β1 and cell contact disruption, through signaling events targeting the serum response factor-myocardin-related transcription factor (MRTF) complex. MRTFs are important regulators of fibrosis, tumor cell invasion, and metastasis. Consistent with the role of MRTFs in tumor progression, suppressor of cancer cell invasion (SCAI) was recently identified as a negative regulator of MRTF. Herein, we studied the role of SCAI in a fibrotic EMT model established on LLC-PK1 cells. SCAI overexpression prevented SMA promoter activation induced by TGF-β1. When co-expressed, it inhibited the stimulatory effects of MRTF-A, MRTF-B or the constitutive active forms of RhoA, Rac1, or Cdc42 on the SMA promoter. SCAI interfered with TGF-β1-induced SMA, connective tissue growth factor, and calponin protein expression; it rescued TGF-β1-induced E-cadherin down-regulation. IHC studies on human kidneys showed that SCAI expression is reduced during fibrosis. Kidneys of diabetic rats and mice with unilateral ureteral obstruction depicted significant loss of SCAI expression. In parallel with the decrease of SCAI protein expression, diabetic rat and mouse kidneys with unilateral ureteral obstruction showed SMA expression, as evidenced by using Western blot analysis. Finally, TGF-β1 treatment of LLC-PK1 cells attenuated SCAI protein expression. These data suggest that SCAI is a novel transcriptional cofactor that regulates EMT and renal fibrosis.
authors.affiliation: 2(nd) Department of Pathology, Semmelweis University, 1089 Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Fintha
authors.forename: Ákos
authors.initials: Á
authors.lastname: Gasparics
authors.forename: Lilla
authors.initials: L
authors.lastname: Fang
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Erdei
authors.forename: Péter
authors.initials: P
authors.lastname: Hamar
authors.forename: Miklós M
authors.initials: MM
authors.lastname: Mózes
authors.forename: Gábor
authors.initials: G
authors.lastname: Kökény
authors.forename: László
authors.initials: L
authors.lastname: Rosivall
authors.forename: Attila
authors.initials: A
authors.lastname: Sebe
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D018374:LLC-PK1 Cells; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013552:Swine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000096985:Calponins
chemical_list: D000199:Actins; D015820:Cadherins; D002135:Calcium-Binding Proteins; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000096985:Calponins; C540922:SCAI protein, human; C498862:Acta2 protein, rat