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SREBP-1 is a novel mediator of TGFβ1 signaling in mesangial cells Free
Guang Chen, Tony Wang, Lalita Uttarwar, Richard vanKrieken, Renzhong Li, Xing Chen, Bo Gao, Ayesha Ghayur, Peter Margetts, and Joan C. Krepinsky*
Division of Nephrology, McMaster University, Hamilton, Canada *Correspondence to:Joan C. Krepinsky, E-mail: krepinj@mcmaster.ca
J Mol Cell Biol, Volume 6, Issue 6, December 2014, Pages 516-530  https://doi.org/10.1093/jmcb/mju041
Keyword: SREBP-1, TGFβ, Smad3, fibrosis, acetylation

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.