[HTML][HTML] TGF-β-mediated upregulation of Sox9 in fibroblast promotes renal fibrosis

H Li, H Cai, J Deng, X Tu, Y Sun, Z Huang… - … Et Biophysica Acta (BBA …, 2018 - Elsevier
H Li, H Cai, J Deng, X Tu, Y Sun, Z Huang, Z Ding, L Dong, J Chen, Y Zang, J Zhang
Biochimica Et Biophysica Acta (BBA)-Molecular Basis of Disease, 2018Elsevier
TGF-β signaling plays a principal role in renal fibrosis, but the precise mechanisms and the
downstream factors are still largely unknown. Sox9 exhibits diverse roles in regulating the
production of extracellular matrix proteins. Here we found that Sox9 was induced by TGF-β
in the kidney fibroblast and acted as an important downstream mediator of TGF-β signaling
in promoting renal fibrosis. TGF-β/Smad signaling mediated the upregulation of Sox9 in
kidney fibroblast by binding to a conserved enhancer. In different mouse models of renal …
Abstract
TGF-β signaling plays a principal role in renal fibrosis, but the precise mechanisms and the downstream factors are still largely unknown. Sox9 exhibits diverse roles in regulating the production of extracellular matrix proteins. Here we found that Sox9 was induced by TGF-β in the kidney fibroblast and acted as an important downstream mediator of TGF-β signaling in promoting renal fibrosis. TGF-β/Smad signaling mediated the upregulation of Sox9 in kidney fibroblast by binding to a conserved enhancer. In different mouse models of renal fibrosis, as well as in the kidney biopsy tissue from patients with renal fibrosis, Sox9 expression significantly increased. Immunostaining confirmed the upregulation of Sox9 in the kidney fibroblast during renal fibrosis. Delivery of Sox9 knockdown plasmid to the kidney by ultrasound microbubble–mediated gene transfer suppressed the unilateral ureteral obstruction (UUO) or folic acid-induced mouse renal fibrosis, whereas ectopic expression of Sox9 aggravated renal fibrosis. In addition, we identified Sox9 as a direct target of miR-30. Notably, miR-30 expression was significantly inhibited by TGF-β1 in the kidney fibroblast and the downregulation of miR-30 was observed in renal fibrosis. Mechanistically, inhibition of miR-30 independently strengthened the effect of TGF-β/Smad signaling on Sox9 upregulation. Adenovirus-mediated ectopic expression of miR-30 in kidney fibroblast greatly reduced UUO-induced renal fibrosis by targeting Sox9. These findings link Sox9 to intrinsic mechanisms of TGF-β signaling in renal fibrosis and may have therapeutic potential for tissue fibrosis.
Elsevier