title: SREBP-1 is a novel mediator of TGFβ1 signaling in mesangial cells.
abstract: Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent studies showed that overexpression of the transcription factor SREBP-1 induces glomerulosclerosis. TGFβ1 is a key profibrotic mediator of glomerulosclerosis, but whether SREBP-1 regulates its effects is unknown. In kidney mesangial cells and in vivo, TGFβ1 activates SREBP-1. This requires SCAP, S1P, and PI3K/Akt signaling, but is independent of Smad3. Activation of the TGFβ1-responsive reporter plasmid p3TP-lux requires SREBP-1a, but not SREBP-1c, binding to an E-box adjacent to a Smad-binding element. SREBP-1a overexpression alone activates p3TP-lux. Smad3 is required for SREBP-1a transcriptional activation and TGFβ1 induces association between the two transcription factors. SREBP-1a K333 acetylation by the acetyltransferase CBP is required for Smad3 association and SREBP-1 transcriptional activity, and is also required for Smad3 transcriptional activity. Thus, both Smad3 and SREBP-1a activation cooperatively regulate TGFβ transcriptional responses. SREBP-1 inhibition provides a novel therapeutic strategy for diabetic kidney disease.
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Wang
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Lalita
authors.initials: L
authors.lastname: Uttarwar
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: vanKrieken
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Renzhong
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Ghayur
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Margetts
authors.affiliation: Division of Nephrology, McMaster University, Hamilton, Canada krepinj@mcmaster.ca.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Krepinsky
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1
keywords: SREBP-1; Smad3; TGFβ; acetylation; fibrosis