Abstract：
Renal ischemia-reperfusion injury (IRI) is an integral process in renal transplantation, which results in compromised graft survival. Macrophages play an important role in both the early inflammatory period and late fibrotic period in response to IRI. In this study, we investigated whether scutellarin (SCU) could protect against renal IRI by regulating macrophage polarization. Mice were given SCU (5-50 mg/kg) by gavage 1 h earlier, followed by a unilateral renal IRI. Renal function and pathological injury were assessed 24 h after reperfusion. The results showed that administration of 50 mg/kg SCU significantly improved renal function and renal pathology in IRI mice. In addition, SCU alleviated IRI-induced apoptosis. Meanwhile, it reduced macrophage infiltration and inhibited pro-inflammatory macrophage polarization. Moreover, in RAW 264.7 cells and primary bone marrow-derived macrophages (BMDMs) exposed to SCU, we found that 150 μM SCU inhibited these cells to polarize to an inflammatory phenotype induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, SCU has no influence on anti-inflammatory macrophage polarization in vivo and in vitro induced by in interleukin-4 (IL-4). Finally, we explored the effect of SCU on the activation of the mitogen-activated protein kinase (MAPK) pathway both in vivo and in vitro. We found that SCU suppressed the activation of the MAPK pathway, including the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38. Our results demonstrated that SCU protects the kidney against IRI by inhibiting macrophage infiltration and polarization toward pro-inflammatory phenotype via the MAPK pathway, suggesting that SCU may be therapeutically important in treatment of IRI.
摘要：
肾缺血再灌注损伤(IRI)是肾移植的一个重要过程,导致移植物存活受损。巨噬细胞在响应IRI的早期炎症期和晚期纤维化期均起重要作用。在这项研究中,我们研究了灯盏乙素（SCU）是否可以通过调节巨噬细胞极化来预防肾脏IRI。1小时前通过管饲法给予小鼠SCU（5-50mg/kg），其次是单侧肾IRI。再灌注后24h评估肾功能和病理损伤。结果表明，50mg/kg的SCU可明显改善IRI小鼠的肾功能和肾脏病理。此外,SCU减轻IRI诱导的细胞凋亡。同时,它减少巨噬细胞浸润和抑制促炎巨噬细胞极化。此外，在暴露于SCU的RAW264.7细胞和原代骨髓源性巨噬细胞（BMDM）中，我们发现150μMSCU抑制这些细胞分化为脂多糖（LPS）和干扰素-γ（IFN-γ）诱导的炎症表型。然而,SCU对白介素-4（IL-4）诱导的体内和体外抗炎巨噬细胞极化没有影响。最后,我们在体内和体外研究了SCU对丝裂原活化蛋白激酶（MAPK）通路激活的影响。我们发现SCU抑制了MAPK通路的激活，包括细胞外信号调节激酶（ERK），Jun氨基末端激酶（JNK），p38我们的结果表明，SCU通过MAPK通路抑制巨噬细胞浸润和向促炎表型的极化来保护肾脏免受IRI，提示SCU在IRI的治疗中可能具有重要的治疗意义。
