Peroxisome proliferator‐activated receptor delta protects against obesity‐related glomerulopathy through the P38 MAPK pathway

Laboratory Investigation

et al. 2016

The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

Section: Discussionmentioning

confidence: 99%

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Laboratory Investigation

et al. 2016

“…The MAPK pathway has also been shown to play an important role in obesity and its activation has been implicated in obesity-related complications such as ORG (Yan et al, 2013). JNK, p38, and ERK, the three main subfamilies of MAPKs, have all been reported to be activated in response to inflammatory and stress-inducing stimuli.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mitogen-Activated Protein Kinases/Nuclear Factor κB–Dependent Inflammation by a Novel Chalcone Protects the Kidney from High Fat Diet–Induced Injuries in Mice

Fang

Deng

et al. 2015

J Pharmacol Exp Ther

The prevalence of obesity has increased dramatically worldwide leading to increases in obesity-related complications, such as obesity-related glomerulopathy (ORG). Obesity is a state of chronic, low-grade inflammation, and increased inflammation in the adipose and kidney tissues has been shown to promote the progression of renal damage in obesity. Current therapeutic options for ORG are fairly limited and, as a result, we are seeing increased rates of progression to end-stage renal disease. Chalcones are a class of naturally occurring compounds with various pharmacological properties. 1-(3,4-Dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one (L2H17) is a chalcone that we have previously synthesized and found capable of inhibiting the lipopolysaccharide-induced inflammatory response in macrophages. In this study, we investigated L2H17's effect on obesityinduced renal injury using palmitic acid-induced mouse peritoneal macrophages and high fat diet-fed mice. Our results indicate that L2H17 protects against renal injury through the inhibition of the mitogen-activated protein kinase/ nuclear factor kB pathways significantly by decreasing the expression of proinflammatory cytokines and cell adhesion molecules and improving kidney histology and pathology. These findings lead us to believe that L2H17, as an antiinflammatory agent, can be a potential therapeutic option in treating ORG.

“…Consistent with this, the PPAR-g agonist rosiglitazone has been shown to downregulate gonadotropin-releasing hormone-mediated phosphorylation of p38 MAPKs in LbT2 cells (Sakaida et al, 2004). In addition, Yan et al (2013) reported that obesity-related glomerulopathy may be caused in part by suppressed PPAR-g expression and increased p38 MAPK activation. Accordingly, we hypothesized that HSYA ameliorated hepatic fibrosis through regulation of the PPAR-g/p38 MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling

Liu

Liu

et al. 2014

Pharmaceutical Biology

Context: One approach to protect against liver fibrosis is the use of herb-derived natural compounds, such as hydroxysafflor yellow A (HSYA). The antifibrosis effect of HYSA against liver fibrosis has been investigated; however, its mechanisms have not yet been entirely revealed. Objectives: To study the protective effects of HSYA on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and a high-fat diet (HFD), and to determine the mechanism of action of HSYA. Materials and methods: CCl 4 and HFD were used to mimic liver fibrosis in rats, and serum biochemical indicators were determined. The antifibrosis effects of HSYA were evaluated and its mechanisms were investigated by histopathological analysis, immunohistochemical staining, enzyme-linked immunosorbent assays, real-time-PCR, and western blotting. Results: HSYA reduced CCl 4 -and HFD-mediated liver fibrosis and ameliorated serum biochemical indicator, downregulated the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (0.31 ± 0.03 protein, 0.59 ± 0.02 mRNA) and transformin growth factor-b1 (TGF-b1) (0.81 ± 0.02 protein, 0.58 ± 0.04 mRNA), and upregulated the expression of peroxisome proliferator-activated receptor-g (PPAR-g) (1.57 ± 0.13 protein, 2.48 ± 0.19 mRNA) and matrix metallopeptidases-2 (MMP-2) (2.31 ± 0.16 protein, 2.79 ± 0.22 mRNA) (p50.01, versus model group). These effects were significantly attenuated by PPAR-g antagonist GW9662 via blocking the phosphorylation of p38 MAPK. Discussion and conclusion: These data demonstrate a novel role for HSYA in inhibiting CCl 4 -and HFD-mediated liver fibrosis, and reveal that PPAR-g and p38 MAPK signaling play pivotal roles in the prevention of liver fibrosis induced by CCl 4 and HFD.