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急性肾损伤（acute renal injury，AKI）和慢性肾脏病引发间质性炎症进展的肾小管间质特征主要为病理性纤维化，这是多种组织器官衰竭的先兆和驱动因素。而肾损伤最常见的原因之一肾缺氧不仅是AKI的关键原因，也是AKI病理生理学向慢性肾病转变的关键因素。在肾脏内，肾小管上皮细胞（renaltubular epithelial cells，TECs）特别容易受到缺血、缺氧、阻塞和代谢损伤。有研究发现，巨噬细胞的缺失可以保护肾脏免受缺氧损伤。然而，人们对低氧TECs激活巨噬细胞的分子信号仍然不清楚。 多项研究在组织细胞分泌的外泌体中观察到miRNAs，对受体细胞发挥调节作用，表明miRNAs的外泌体转移可能是细胞间通讯的新机制。近日，来自东南大学中大医院的研究人员证明了从HIF-1a激活的TECs释放的富含miRNA-23a的外泌体通过抑制泛素编辑蛋白A20的活性，重编程巨噬细胞表型。该研究在缺血/再灌注损伤和单侧输尿管梗阻的小鼠模型中证实了肾小管间质炎症和肾小管HIF-1α表达增加。管状上皮细胞中HIF-1α的表达增加与体内富含miRNA-23a外泌体的释放相关，并且在缺血/再灌注损伤之前miRNA-23a的全身抑制减弱了肾小管间质炎症。在体外，巨噬细胞对富含miRNA-23a的外泌体的摄取通过抑制泛素蛋白编辑蛋白A20触发其重编程为促炎状态。为了证实含有miRNA-23a的外泌体对肾小管间质炎症的影响，该研究将TECs暴露于低氧条件以促进含有miRNA-23a的外泌体释放。结果显示，将这些富含miRNA-23a的外泌体注射到未受损的肾实质中会导致体内炎症浸润增加。 该研究表明，富含miRNA-23a外泌体的HIF-1α依赖性释放来自缺氧肾小管上皮细胞。在管状上皮细胞和巨噬细胞之间阻断外泌体介导的miRNA-23a转移为改善肾小管间质炎症新型疗法提供治疗靶点。
推荐阅读原文：
HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation.
Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1α modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1α expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1α 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-1α-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosome-mediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation.
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