Scutellarin alleviates renal ischemia–reperfusion injury by inhibiting the MAPK pathway and pro‐inflammatory macrophage polarization

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.