Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes

Scientific Reports
Imari MimuraMasaomi Nangaku

Abstract

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. ...Continue Reading

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Citations

Nov 1, 2018·American Journal of Physiology. Renal Physiology·Alice DoreilleHeloise Cardinal
Jan 18, 2019·Nature Reviews. Nephrology·Chunyuan GuoZheng Dong
Jan 30, 2021·Diabetes & Metabolism Journal·Tomotaka YamazakiMasaomi Nangaku

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Datasets Mentioned

BETA
DRA003787

Methods Mentioned

BETA
RNA-seq
laser-capture microdissection
ChIP

Software Mentioned

DZNep
DAVID
Database for Annotation , Visualization and Integrated Discove...
Affymetrix

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