Reducing inflammatory cytokine production from renal collecting duct cells by inhibiting GATA2 ameliorates acute kidney injury

Lei Yu, Takashi Moriguchi, Hiroshi Kaneko, Makiko Hayashi, Atsushi Hasegawa, Masahiro Nezu, Hideyuki Saya, Masayuki Yamamoto, Ritsuko Shimizu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

Original languageEnglish
Article numbere00211-17
JournalMolecular and Cellular Biology
Volume37
Issue number22
DOIs
Publication statusPublished - 2017 Nov 1

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Acute Kidney Injury
Cytokines
Kidney
Reperfusion Injury
Collecting Kidney Tubules
GATA2 Transcription Factor
Small Molecule Libraries
Gene Expression Profiling
Chronic Renal Insufficiency
Down-Regulation
Gene Expression
Genes

Keywords

  • Acute kidney disease
  • Gata2
  • Inflammation
  • Kidney

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Reducing inflammatory cytokine production from renal collecting duct cells by inhibiting GATA2 ameliorates acute kidney injury. / Yu, Lei; Moriguchi, Takashi; Kaneko, Hiroshi; Hayashi, Makiko; Hasegawa, Atsushi; Nezu, Masahiro; Saya, Hideyuki; Yamamoto, Masayuki; Shimizu, Ritsuko.

In: Molecular and Cellular Biology, Vol. 37, No. 22, e00211-17, 01.11.2017.

Research output: Contribution to journalArticle

Yu, Lei ; Moriguchi, Takashi ; Kaneko, Hiroshi ; Hayashi, Makiko ; Hasegawa, Atsushi ; Nezu, Masahiro ; Saya, Hideyuki ; Yamamoto, Masayuki ; Shimizu, Ritsuko. / Reducing inflammatory cytokine production from renal collecting duct cells by inhibiting GATA2 ameliorates acute kidney injury. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 22.
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