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IRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress.

ABSTRACT: Particulate matter (PM2.5) is a risk factor for organ injury and disease progression, such as lung, brain and liver. However, its effects on renal injury and the underlying molecular mechanism have not been understood. The inactive rhomboid protein 2 (iRhom2), also known as rhomboid family member 2 (Rhbdf2), is a necessary modulator for shedding of tumor necrosis factor-? (TNF-?) in immune cells, and has been explored in the pathogenesis of chronic renal diseases. In the present study, we found that compared to the wild type (iRhom2^+/+) mice, iRhom2 knockout (iRhom2^-/-) protected PM_2.5-exposed mice from developing severe renal injury, accompanied with improved renal pathological changes and functions. iRhom2^-/- mice exhibited reduced inflammatory response, as evidenced by the reduction of interleukin 1? (IL-1?), IL-6, tumor necrosis factor-? (TNF-?) and IL-18 in kidney samples, which might be, at least partly, through inactivating TNF-? converting enzyme/TNF-? receptors (TACE/TNFRs) and inhibitor of ?/nuclear factor ? B (I?B?/NF-?B) signaling pathways. In addition, oxidative stress was also restrained by iRhom2^-/- in kidney of PM_2.5-exposed mice by enhancing heme oxygenase/nuclear factor erythroid 2-related factor 2 (HO-1/Nrf-2) expressions, and reducing phosphorylated c-Jun N-terminal kinase (JNK). In vitro, blockage of HO-1 or Nrf-2 rescued the inflammatory response and oxidative stress that were reduced by iRhom2 knockdown in PM_2.5-incubated RAW264.7 cells. Similar results were observed in JNK activator-treated cells. Taken together, our findings indicated that iRhom2 played an essential role in regulating PM_2.5-induced chronic renal damage, thus revealing a potential target for preventing chronic kidney diseases development.

SUBMITTER: Chenxu G

PROVIDER: S-EPMC6118040 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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iRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress.

Chenxu Ge G Minxuan Xu X Yuting Qin Q Tingting Gu G Jinxiao Lv L Mingxing Wang W Sujun Wang W Yongjie Ma M Deshuai Lou L Qiang Li L Linfeng Hu H Jun Tan T

Redox biology 20180820

Particulate matter (PM2.5) is a risk factor for organ injury and disease progression, such as lung, brain and liver. However, its effects on renal injury and the underlying molecular mechanism have not been understood. The inactive rhomboid protein 2 (iRhom2), also known as rhomboid family member 2 (Rhbdf2), is a necessary modulator for shedding of tumor necrosis factor-α (TNF-α) in immune cells, and has been explored in the pathogenesis of chronic renal diseases. In the present study, we found ...[more]

PMID: 30165303

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Project description:BackgroundAcute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms.MethodsFor drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3).ResultsFGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis.ConclusionsAltogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

Dataset Information

IRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress.

Publications

iRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress.

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