RESUMEN
Renal ischemia-reperfusion injury (IRI) is one of the most important causes of acute kidney injury (AKI). Interleukin (IL)-37 has been suggested as a novel anti-inflammatory factor for the treatment of IRI, but its application is still limited by its low stability and delivery efficiency. In this study, we reported a novel engineered method to efficiently and easily prepare neutrophil membrane-derived vesicles (N-MVs), which could be utilized as a promising vehicle to deliver IL-37 and avoid the potential side effects of neutrophil-derived natural extracellular vesicles. N-MVs could enhance the stability of IL-37 and targetedly deliver IL-37 to damaged endothelial cells of IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). In vitro and in vivo evidence revealed that N-MVs encapsulated with IL-37 (N-MV@IL-37) could inhibit endothelial cell apoptosis, promote endothelial cell proliferation and angiogenesis, and decrease inflammatory factor production and leukocyte infiltration, thereby ameliorating renal IRI. Our study establishes a promising delivery vehicle for the treatment of renal IRI and other endothelial damage-related diseases.
Asunto(s)
Células Endoteliales , Interleucina-1 , Riñón , Neutrófilos , Daño por Reperfusión , Animales , Daño por Reperfusión/tratamiento farmacológico , Interleucina-1/administración & dosificación , Masculino , Humanos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Riñón/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Glicoproteínas de Membrana/administración & dosificación , Proliferación Celular/efectos de los fármacos , Lesión Renal Aguda , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/químicaRESUMEN
OBJECTIVE: Ischemic preconditioning (IPC) is defined as a well-established phenomenon in which brief exposure to sublethal episodes of ischemia and reperfusion induces a tolerance to injurious effects of prolonged ischemia by exploiting intrinsic defence mechanisms. The present study was performed to determine the protective effect of IPC on the rat renal ischemia-reperfusion injury (IRI) via miR-376c-3p/HIF-1α/VEGF axis. METHODS: In vivo, these male Sprague-Dawley rats were treated by IRI and IPC. Meanwhile, these rats from different treatment groups were also injected subcutaneously with 2â¯nmol agomir-376c-3p and/or 10â¯nmol recombinant rat HIF-1α. At 72â¯h after reperfusion, serum samples were respectively collected for renal function. Besides, kidney tissues were harvested to observe renal morphology changes. Subsequently, the expression levels of CD31, HIF-1α and VEGF in the kidney tissues were measured using immunohistochemical staining, quantitative real-time PCR, as well as Western blotting analysis at the indicated time points after reperfusion. In vitro, HK-2 cells were used to detect the cell activity by CCK-8 and transfection of mir-376c-3p mimic in Hypoxia/Reoxygenation (H/R) group. RESULTS: In vivo, the pathological changes were significantly relieved in the rats with IPC group, compared to the IRI group. Rats which were treated IPC significantly reduced the levels of blood urea nitrogen (BUN), serum creatinine (Scr) at 24â¯h after operation, compared to IRI group. After IPC treatment, the expression level of CD31 was obviously decreased, compared to IRI group. A total of differently expressed microRNAs were screened out by microRNA microarray assay in rat renal ischemia tissue, especially showing that miR-376c-3p was selected as the target miRNA. Compared to IRI group, the expression level of miR-376c-3p were obviously higher in IPC-treated group. Double-luciferase reporter assay demonstrated that miR-376c-3p directly targeted HIF-1α. In vitro, IPC significantly increased cell viability of HK-2, and promoted the angiogenesis via up-regulating miR-376c-3p/HIF-1α/VEGF axis. Furthermore, the expression level of HIF-1α was apparently decreased in HK-2 treated with H/R after miR-376c-3p mimic transfection respectively, as well as the increased expression level of VEGF. CONCLUSIONS: Our study provided a novel insight for investigating the protective effect of IPC on renal IRI. Consequently, miR-376c-3p played an important role in renal IRI by promoting angiogenesis via targeting HIF-1α/VEGF pathway in male rats.