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.  

J Mol Cell Biol mju041 first published online October 26, 2014 doi:10.1093/jmcb/mju041            

Keywords: SREBP-1, TGFβ, Smad3, fibrosis, acetylation  

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Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation  

Abstract
Enzymes involved in collagen biosynthesis, including lysyl oxidase (LOX), have been proposed
as potential therapeutic targets for idiopathic pulmonary fibrosis. LOX expression is significantly
upregulated in belomycin (BLM)-induced lung fibrosis, and knockdown of LOX expression or
inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with
LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen
deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory cell
infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expression
of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung
fibrosis. These results suggest that LOX is indispensible for the progression of BLM-induced
experimental lung fibrosis by aggravating the inflammatory response and subsequent fibrosis
process after lung injury.

J Mol Cell Biol mju039 first published online October 26, 2014 doi:10.1093/jmcb/mju039

Keywords: lysyl oxidase, lung fibrosis, inflammation, bleomycin, animal models, extracellular matrix