Amrouche Lucile, Desbuissons Geoffroy, Rabant Marion, Sauvaget Virginia, Nguyen Clément, Benon Aurélien, Barre Pauline, Rabaté Clémentine, Lebreton Xavier, Gallazzini Morgan, Legendre Christophe, Terzi Fabiola, Anglicheau Dany
Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
Paris Descartes, Sorbonne Paris Cité University, Paris, France.
J Am Soc Nephrol. 2017 Feb;28(2):479-493. doi: 10.1681/ASN.2016010045. Epub 2016 Jul 21.
AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.
急性肾损伤会导致肾小管损伤和间质炎症，必须对其加以控制以避免纤维化的发展。我们推测，微小RNA参与了损伤形成与适应性修复之间平衡的调节。我们发现，在促炎条件下，白细胞介素-1受体/Toll样受体家族成员的配体通过激活培养的肾近端小管细胞中的核因子κB，使微小RNA-146a（miR-146a）转录上调。在体内，在人肾移植受者的同种异体移植物和尿液中，更严重的肾缺血再灌注损伤（IRI）与miR-146a表达增加相关，并且小鼠单侧IRI可诱导损伤肾脏中miR-146a表达。单侧IRI后，与野生型小鼠相比，miR-146a基因敲除小鼠表现出更广泛的肾小管损伤、炎性浸润和纤维化。在体外，miR-146a的过表达或下调分别减少或增强了白细胞介素-1受体相关激酶1的表达，并对损伤的肾小管细胞的C-X-C基序配体8（CXCL8）/CXCL1表达产生了类似影响。此外，抑制CXCL8/CXCL1信号传导可防止miR-146a基因敲除小鼠IRI后炎症和纤维化的发展。总之，这些结果表明，miR-146a是肾小管对IRI反应的关键介质，它限制了炎症的后果，而炎症是急性肾损伤和慢性肾脏病发展的关键过程。
