Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes.
Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes.
复制标题
DOI：
10.1038/s41598-018-22180-5
复制
发表时间：
2018-02-28
影响因子：
4.6
通讯作者：
Nangaku M
中科院分区：
文献类型：
--
作者：
Mimura I;Hirakawa Y;Kanki Y;Nakaki R;Suzuki Y;Tanaka T;Aburatani H;Nangaku M
肾小管间质纤维化是由肾脏疾病的表观遗传调控机制紊乱引起的。我们研究了组蛋白修饰的药理学抑制是否对肾纤维化有效。DZNep（3-deazaneplanocin A）最初是作为一种抗癌药物开发的，用于抑制抑制组蛋白标记H3 K27 me 3。我们使用了由单侧缺血/再灌注诱导的慢性肾小管间质纤维化模型，并将DZNep静脉内给予小鼠8周。我们发现DZNep有助于减少肾小管间质纤维化。我们使用激光捕获显微切割从体内样品中仅选择肾小管细胞，因为表观遗传调节对细胞类型是特异性的，并且我们专注于肾小管细胞的变化。我们使用高通量测序（RNA-seq）对肾小管细胞进行了全基因组分析，以确定与肾纤维化相关的新表观遗传因素。我们发现，促纤维化基因，如COL 3A 1（3a 1型胶原）和TIMP 2（金属蛋白酶组织抑制剂2）被DZNep体内抑制。此外，DZNep在体外下调促纤维化基因如COL 4A 1（胶原4a 1型）、TIMP 2和MMP 14。总之，我们发现DZNep的药理学表观遗传修饰降低了肾小管细胞中致纤维化基因的表达水平，并抑制了肾小管间质纤维化。
Tubulointerstitial fibrosis has been recently reported to be caused by the collapse of the epigenetic regulation of kidney diseases. We examined whether pharmacological inhibition of histone modification is effective against renal fibrosis. DZNep (3-deazaneplanocin A) was originally developed as an anti-cancer drug to inhibit the repressive histone mark, H3K27me3. We used a model of chronic tubulointerstitial fibrosis induced by unilateral ischaemia/reperfusion and administered DZNep intravenously to the mice for 8 weeks. We found DZNep contributes to the reduction of tubulointerstitial fibrosis. We selected only tubular cells from in vivo samples using laser-capture microdissection because epigenetic regulation is specific to the cell types, and we focused on the changes in the tubular cells. We performed a genome-wide analysis of tubular cells using high-throughput sequencing (RNA-seq) to identify novel epigenetic factors associated with renal fibrosis. We found that pro-fibrotic genes such as COL3A1 (collagen type 3a1) and TIMP2 (tissue inhibitor of metalloproteinase 2) were suppressed by DZNep in vivo. In addition, pro-fibrotic genes such as COL4A1 (collagen type 4a1), TIMP2 and MMP14 were down-regulated by DZNep in vitro. In conclusion, we found that pharmacological epigenetic modification by DZNep decreased the expression levels of fibrogenic genes in tubular cells and inhibited tubulointerstitial fibrosis.
登录
查看更多内容
DOI：
10.1074/jbc.m114.548651
发表时间：
2014-03-21
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fujiwara T;Saitoh H;Inoue A;Kobayashi M;Okitsu Y;Katsuoka Y;Fukuhara N;Onishi Y;Ishizawa K;Ichinohasama R;Harigae H
通讯作者：
Harigae H
影响因子：
2.5
作者：
Xiao X;Senavirathna LK;Gou X;Huang C;Liang Y;Liu L
通讯作者：
Liu L
DOI：
10.1073/pnas.88.19.8725
发表时间：
1991-10-01
影响因子：
11.1
作者：
SEMENZA, GL;KOURY, ST;ANTONARAKIS, SE
通讯作者：
ANTONARAKIS, SE
影响因子：
4.1
作者：
Bernardo, MM;Fridman, R
通讯作者：
Fridman, R
影响因子：
27.4
作者：
Kraemer, Marlene;Dees, Clara;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.