Endothelin-converting enzyme is a plausible target gene for hypoxia-inducible factor

Mogher Khamaisi, Hala Toukan, Jonathan H. Axelrod, Christian Rosenberger, Galia Skarzinski, Ahuva Shina, Rina Meidan, Robert Koesters, Seymour Rosen, Gail Walkinshaw, Imari Mimura, Masaomi Nangaku, Samuel N. Heyman

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Renal endothelin-converting enzyme (ECE)-1 is induced in experimental diabetes and following radiocontrast administration, conditions characterized by renal hypoxia, hypoxia-inducible factor (HIF) stabilization, and enhanced endothelin synthesis. Here we tested whether ECE-1 might be a HIF-target gene in vitro and in vivo. ECE-1 transcription and expression increased in cultured vascular endothelial and proximal tubular cell lines, subject to hypoxia, to mimosine or cobalt chloride. These interventions are known to stabilize HIF signaling by inhibition of HIF-prolyl hydroxylases. In rats, HIF-prolyl-hydroxylase inhibition by mimosine or FG-4497 increased HIF-1α immunostaining in renal tubules, principally in distal nephron segments. This was associated with markedly enhanced ECE-1 protein expression, predominantly in the renal medulla. A progressive and dramatic increase in ECE-1 immunostaining over time, in parallel with enhanced HIF expression, was also noted in conditional von Hippel-Lindau knockout mice. Since HIF and STAT3 are cross-stimulated, we triggered HIF expression by STAT3 activation in mice, transfected by or injected with a chimeric IL-6/IL-6-receptor protein, and found a similar pattern of enhanced ECE-1 expression. Chromatin immunoprecipitation sequence (ChIP-seq) and PCR analysis in hypoxic endothelial cells identified HIF binding at the ECE-1 promoter and intron regions. Thus, our findings suggest that ECE-1 may be a novel HIF-target gene.

Original languageEnglish
Pages (from-to)761-770
Number of pages10
JournalKidney International
Volume87
Issue number4
DOIs
StatePublished - 8 Apr 2015
Externally publishedYes

Keywords

  • Endothelin
  • HIF-1
  • Hypoxia
  • Kidney

ASJC Scopus subject areas

  • Nephrology

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