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2017 ; 5
(8
): ä Nephropedia Template TP
gab.com Text
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Novel lnc RNA regulated by HIF-1 inhibits apoptotic cell death in the renal
tubular epithelial cells under hypoxia
#MMPMID28420760
Mimura I
; Hirakawa Y
; Kanki Y
; Kushida N
; Nakaki R
; Suzuki Y
; Tanaka T
; Aburatani H
; Nangaku M
Physiol Rep
2017[Apr]; 5
(8
): ä PMID28420760
show ga
Chronic tubulointerstitial hypoxia plays an important role as the final common
pathway to end-stage renal disease. HIF-1 (hypoxia-inducible factor-1) is a
master transcriptional factor under hypoxia, regulating downstream target genes.
Genome-wide analysis of HIF-1 binding sites using high-throughput sequencers has
clarified various kinds of downstream targets and made it possible to demonstrate
the novel roles of HIF-1. Our aim of this study is to identify novel HIF-1
downstream epigenetic targets which may play important roles in the kidney.
Immortalized tubular cell lines (HK2; human kidney-2) and primary cultured cells
(RPTEC; renal proximal tubular cell lines) were exposed to 1% hypoxia for
24-72 h. We performed RNA-seq to clarify the expression of mRNA and long
non-coding RNA (lncRNA). We also examined ChIP-seq to identify HIF-1 binding
sites under hypoxia. RNA-seq identified 44 lncRNAs which are up-regulated under
hypoxic condition in both cells. ChIP-seq analysis demonstrated that HIF-1 also
binds to the lncRNAs under hypoxia. The expression of novel lncRNA, DARS-AS1
(aspartyl-tRNA synthetase anti-sense 1), is up-regulated only under hypoxia and
HIF-1 binds to its promoter region, which includes two hypoxia-responsive
elements. Its expression is also up-regulated with cobalt chloride exposure,
while it is not under hypoxia when HIF-1 is knocked down by siRNA To clarify the
biological roles of DARS-AS1, we measured the activity of caspase 3/7 using
anti-sense oligo of DARS-AS1. Knockdown of DARS-AS1 deteriorated apoptotic cell
death. In conclusion, we identified the novel lncRNAs regulated by HIF-1 under
hypoxia and clarified that DARS-AS1 plays an important role in inhibiting
apoptotic cell death in renal tubular cells.
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