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

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.

Deng G ，Zheng B ，Dou M ，Gao Y ，Zhang X ，Niu Z ，Wei T ，Han F ，Ding C ，Tian P ... -  《-》

[Scutellarin alleviates lipopolysaccharide-induced renal injury via mediating cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 expression to inhibit nuclear factor-κB signaling pathway].

Liu X ，Qin Z ，Guan C ，Xu L ，Dai J ，Yang C ，Zhou B ，Luan H ，Zhao L ，Zhang W ，Luo C ，Xu Y ... -  《-》

Trans-cinnamaldehyde attenuates renal ischemia/reperfusion injury through suppressing inflammation via JNK/p38 MAPK signaling pathway.

Inflammation is the major contributor to the mechanisms of acute kidney injury due to renal ischemia-reperfusion injury (IRI). Trans-cinnamaldehyde (TCA) is a main bioactive component extracted from the bark of cinnamon and has been proved to have good anti-inflammatory properties. The current study was to demonstrate the effect of TCA on renal IRI and explore its specific mechanism. C57BL/6J mice were injected prophylactically intraperitoneally for TCA 3 days, and IRI for 24 h. In parallel, Human Kidney-2 (HK-2) cells were prophylactically treated with TCA, and then exposed to oxygen glucose deprivation/reperfusion (OGD/R) and cobalt chloride (CoCl2). TCA was found to significantly attenuate renal pathological changes and renal dysfunction, and inhibit gene and protein expression of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, TCA significantly suppressed the expression of TNF-α, IL-6, IL-1β, COX-2, iNOS, and MCP-1. Mechanistically, the activation of the JNK/p38 MAPK signaling pathway was inhibited by TCA in renal IRI as well as in OGD/R and CoCl2-stimulated cells. However, following pretreatment with anisomycin before OGD/R treatment, we found that the activation of the JNK/p38 MAPK signaling pathway was significantly enhanced, and concomitant abrogation of the TCA inhibitory effect on the JNK/p38 MAPK signaling pathway, which was followed by a worsening of cell injury that was characterized by an increased number of cell necrosis and an increase in the expression of Kim-1, NGAL as well as proinflammatory factors (IL-6, IL-1β, iNOS). In summary, TCA inhibited renal inflammation via the JNK/p38 MAPK signaling pathway and attenuated renal IRI.

Chen L ，Yuan J ，Li H ，Ding Y ，Yang X ，Yuan Z ，Hu Z ，Gao Y ，Wang X ，Lu H ，Cai Y ，Bai Y ，Pan X ... -  《-》

Formononetin Alleviates Ischemic Acute Kidney Injury by Regulating Macrophage Polarization through KLF6/STAT3 Pathway.

Zhang NX ，Guan C ，Li CY ，Xu LY ，Xin YL ，Song Z ，Li TY ，Yang CY ，Zhao L ，Che L ，Wang YF ，Man XF ，Xu Y ... -  《-》

Inhibition of IL-18 reduces renal fibrosis after ischemia-reperfusion.

Acute kidney injury induced by ischemia-reperfusion injury (IRI) is a high risk factor in the progression towards chronic kidney disease, which is featured by renal interstitial fibrosis. Interleukin (IL)-18 is produced by T cells and macrophages and has been involved in the pathophysiology of IRI. However, the role of IL-18 in IRI-induced renal fibrosis is poorly understood. In the present study, we showed that interleukin (IL)-18 was significantly up-regulated after IRI stress. Mice treated with IL-18 Bp, a natural inhibitor of IL-18, presented less severe fibrotic response in the kidneys following IRI compared with vehicle-treated mice. Inhibition of IL-18 decreased myofibroblasts formation in the kidneys in response to IRI, which was associated with reduction of fibronectin and collagenⅠproteins. Moreover, inhibition of IL-18 impaired infiltration of CD3+ T cells and F4/80+ macrophages in the kidneys of mice after IRI. Treatment with IL-18 Bp reduces the levels of profibrotic molecules in the kidneys of mice following IRI. Finally, administration of IL-18 Bp impedes the transition of M2 macrophages to myofibroblasts and suppressed the accumulation of bone marrow-derived M2 macrophages. Adoptive transfer of M2 macrophages abolished the anti-fibrotic effect of IL-18 Bp. In summary, our results suggest that IL-18 plays an important role in the progression of IRI-induced renal fibrosis via modulating inflammation cells infiltration, the expression of inflammatory cytokines and chemokines, and the transition of bone marrow-derived M2 macrophages to myofibroblasts.

Liang H ，Xu F ，Zhang T ，Huang J ，Guan Q ，Wang H ，Huang Q ... -  《-》