Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

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.

KEYWORDS:

• Gata2
• kidney
• acute kidney disease
• inflammation

ACKNOWLEDGMENTS

We thank Tomokazu Souma and Norio Suzuki for technical help and scientific comments. We also thank Kowa Pharmaceutical, Inc., for the generous gift of chemical compounds.

This study was supported by JSPS Kakenhi (grant 16H05147 to T.M. and grant 15H02507 to M.Y.), the Kobayashi Foundation for Cancer Research (T.M.), the Platform Project for Supporting Drug Discovery and Life Science Research funded by AMED (M.Y. and R.S.), and a research grant from the Astellas Foundation for Research on Metabolic Disorders (R.S.).