HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation
HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation
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HIF-1α 诱导外泌体 microRNA-23a 表达介导肾小管间质炎症中肾小管上皮细胞和巨噬细胞之间的串扰。
DOI：
10.1016/j.kint.2018.09.013
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发表时间：
2019-02-01
影响因子：
19.6
通讯作者：
Liu, Bi-Cheng
中科院分区：
文献类型：
--
作者：
Li, Zuo-Lin;Lv, Lin-Li;Liu, Bi-Cheng
缺氧会促进肾脏肾小管间质炎症。尽管缺氧诱导因子 1 α (HIF-1 α) 是缺氧反应的主要调节因子，但 HIF-1 α 调节肾小管间质炎症诱导的确切机制仍不清楚。我们在缺血/再灌注损伤和单侧输尿管梗阻的小鼠模型中证明了肾小管间质炎症和肾小管 HIF-1 α 表达增加。肾小管上皮细胞中 HIF-1 α 表达的增加与体内富含 microRNA-23a (miRNA-23a) 的外泌体的选择性脱落以及在缺血/再灌注损伤减轻肾小管间质炎症之前对 miRNA-23a 的全身抑制有关。在体外，巨噬细胞摄取富含 miRNA-23a 的外泌体，通过抑制泛素编辑器 A20 触发其重编程进入促炎状态。为了证实含有 miRNA-23a 的外泌体对肾小管间质炎症的影响，我们将肾小管上皮细胞暴露于缺氧条件下，以促进含有 miRNA-23a 的外泌体的释放。将这些富含 miRNA-23a 的外泌体注射到未受伤的肾实质中导致体内炎症浸润增加。综上所述，我们的研究表明，缺氧肾小管上皮细胞中 HIF-1 α 依赖性释放富含 miRNA-23a 的外泌体可激活巨噬细胞，从而促进肾小管间质炎症。阻断外泌体介导的肾小管上皮细胞和巨噬细胞之间的 miRNA-23a 转移可能作为改善肾小管间质炎症的一种新的治疗方法。
Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1 alpha (HIF-1 alpha) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1 alpha modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1 alpha expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1 alpha in tubular epithelial cells was associated with selective shedding of microRNA-23a (miRNA-23a)-enriched exosomes in vivo and systemic inhibition of miRNA-23a prior to ischemia/reperfusion injury attenuated tubulointerstitial inflammation. In vitro, uptake of miRNA-23a-enriched exosomes by macrophages triggered their reprogramming into a pro-inflammatory state via suppression of the ubiquitin editor A20. To confirm the effect of miRNA-23a-containing exosomes on tubulointerstitial inflammation, we exposed tubular epithelial cells to hypoxic conditions to promote the release of miRNA-23a-containing exosomes. Injection of these miRNA-23a-enriched exosomes into uninjured renal parenchyma resulted in increased inflammatory infiltration in vivo. Taken together, our studies demonstrate that the HIF-1 alpha-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosomemediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation.