急性腎損傷（acute renal injury，AKI）和慢性腎臟病引發(fā)間質(zhì)性炎癥進(jìn)展的腎小管間質(zhì)特征主要為病理性纖維化，這是多種組織器官衰竭的先兆和驅(qū)動因素。而腎損傷最常見的原因之一腎缺氧不僅是AKI的關(guān)鍵原因，也是AKI病理生理學(xué)向慢性腎病轉(zhuǎn)變的關(guān)鍵因素。在腎臟內(nèi)，腎小管上皮細(xì)胞（renaltubular epithelial cells，TECs）特別容易受到缺血、缺氧、阻塞和代謝損傷。有研究發(fā)現(xiàn)，巨噬細(xì)胞的缺失可以保護(hù)腎臟免受缺氧損傷。然而，人們對低氧TECs激活巨噬細(xì)胞的分子信號仍然不清楚。

多項(xiàng)研究在組織細(xì)胞分泌的外泌體中觀察到miRNAs，對受體細(xì)胞發(fā)揮調(diào)節(jié)作用，表明miRNAs的外泌體轉(zhuǎn)移可能是細(xì)胞間通訊的新機(jī)制。近日，來自東南大學(xué)中大醫(yī)院的研究人員證明了從HIF-1a激活的TECs釋放的富含miRNA-23a的外泌體通過抑制泛素編輯蛋白A20的活性，重編程巨噬細(xì)胞表型。該研究在缺血/再灌注損傷和單側(cè)輸尿管梗阻的小鼠模型中證實(shí)了腎小管間質(zhì)炎癥和腎小管HIF-1α表達(dá)增加。管狀上皮細(xì)胞中HIF-1α的表達(dá)增加與體內(nèi)富含miRNA-23a外泌體的釋放相關(guān)，并且在缺血/再灌注損傷之前miRNA-23a的全身抑制減弱了腎小管間質(zhì)炎癥。在體外，巨噬細(xì)胞對富含miRNA-23a的外泌體的攝取通過抑制泛素蛋白編輯蛋白A20觸發(fā)其重編程為促炎狀態(tài)。為了證實(shí)含有miRNA-23a的外泌體對腎小管間質(zhì)炎癥的影響，該研究將TECs暴露于低氧條件以促進(jìn)含有miRNA-23a的外泌體釋放。結(jié)果顯示，將這些富含miRNA-23a的外泌體注射到未受損的腎實(shí)質(zhì)中會導(dǎo)致體內(nèi)炎癥浸潤增加。

該研究表明，富含miRNA-23a外泌體的HIF-1α依賴性釋放來自缺氧腎小管上皮細(xì)胞。在管狀上皮細(xì)胞和巨噬細(xì)胞之間阻斷外泌體介導(dǎo)的miRNA-23a轉(zhuǎn)移為改善腎小管間質(zhì)炎癥新型療法提供治療靶點(diǎn)。

推薦閱讀原文：
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.