RGD Reference Report - Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-ß-mediated Nox4 expression. - Rat Genome Database

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Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-ß-mediated Nox4 expression.

Authors: Zhou, Baoshang  Mu, Jiao  Gong, Yi  Lu, Caibao  Zhao, Youguang  He, Ting  Qin, Zhexue 
Citation: Zhou B, etal., Redox Biol. 2017 Apr;11:390-402. doi: 10.1016/j.redox.2016.12.031. Epub 2016 Dec 30.
RGD ID: 13800569
Pubmed: PMID:28063381   (View Abstract at PubMed)
PMCID: PMC5219604   (View Article at PubMed Central)
DOI: DOI:10.1016/j.redox.2016.12.031   (Journal Full-text)

Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-ß1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-ß1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-ß1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-ß-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ureteral obstruction treatmentISOMapk1 (Rattus norvegicus)13800569; 13800569 RGD 
ureteral obstruction treatmentISOMapk3 (Rattus norvegicus)13800569; 13800569 RGD 
ureteral obstruction treatmentIDA 13800569; 13800569 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mapk1  (mitogen activated protein kinase 1)
Mapk3  (mitogen activated protein kinase 3)

Genes (Mus musculus)
Mapk1  (mitogen-activated protein kinase 1)
Mapk3  (mitogen-activated protein kinase 3)

Genes (Homo sapiens)
MAPK1  (mitogen-activated protein kinase 1)
MAPK3  (mitogen-activated protein kinase 3)

Additional Information