Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury.
Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury.
复制标题
通过抑制 GATA2 减少肾集合管细胞炎症细胞因子的产生可改善急性肾损伤。
DOI：
10.1128/mcb.00211-17
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发表时间：
2017
影响因子：
5.3
通讯作者：
Shimizu R.
中科院分区：
文献类型：
--
作者：
Yu L;Moriguchi T;Kaneko H;Hayashi M;Hasegawa A;Nezu M;Saya H;Yamamoto M;Shimizu R.
急性肾损伤(AKI)是慢性肾脏疾病的主要原因。近端小管被认为是AKI致病性炎性细胞因子的主要来源。然而，目前尚不清楚其他类型的细胞，包括集合管(CD)细胞是否参与炎症过程。转录因子GATA2在CD细胞中特异表达，并维持其细胞特性。为了探讨GATA2在AKI中的病理生理功能，我们建立了肾小管细胞特异性GATA2缺失(G2CKO)小鼠，并检测了它们对缺血再灌注损伤(IRI)的敏感性。值得注意的是，G2CKO小鼠表现出较轻的肾脏损害，IRI时粒-巨噬细胞浸润减少。转录组分析显示，在GATA2缺陷的CD细胞中，一系列炎性细胞因子基因表达下调，提示GATA2诱导了病变肾脏CD细胞中炎性细胞因子的表达。通过高通量化学文库筛选，我们确定了一个有效的GATA抑制剂。这种化学物质减少CD细胞中细胞因子的产生，并保护小鼠肾脏免受IRI的影响。这些结果揭示了肾脏IRI的一种新的病理机制，即CD细胞产生炎性细胞因子并促进IRI的进展。在受损的肾脏CD细胞中，GATA2通过上调炎症细胞因子基因的表达发挥促炎作用。因此，GATA2可以被认为是AKI的治疗靶点。
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-specificGata2deletion (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.