scholarly journals CD36-Mediated Lipid Accumulation and Activation of NLRP3 Inflammasome Lead to Podocyte Injury in Obesity-Related Glomerulopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Zhao ◽  
Hong-liang Rui ◽  
Min Yang ◽  
Li-jun Sun ◽  
Hong-rui Dong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lipid Accumulation ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Animal Experiments ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Podocyte Injury ◽  
Peroxisome Proliferator Activated Receptor

Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

2013 ◽  
Vol 305 (2) ◽  
pp. F143-F154 ◽  
Author(s):  
Harshini Mudaliar ◽  
Carol Pollock ◽  
Muralikrishna Gangadharan Komala ◽  
Steven Chadban ◽  
Huiling Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Responses ◽  
Proximal Tubules ◽  
Peroxisome Proliferator ◽  
Tlr2 Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

scholarly journals SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

2016 ◽  
Vol 36 (7) ◽  
pp. 1180-1193 ◽  
Author(s):  
Nathan L. Price ◽  
Brandon Holtrup ◽  
Stephanie L. Kwei ◽  
Martin Wabitsch ◽  
Matthew Rodeheffer ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Target Genes ◽  
Adipocyte Differentiation ◽  
Regulatory Element ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promotingin vitroadipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precludingin vivoassessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along withSREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells

2006 ◽  
Vol 290 (5) ◽  
pp. E916-E924 ◽  
Author(s):  
Juan Kong ◽  
Yan Chun Li
Keyword(s):  
Cell Differentiation ◽  
Molecular Mechanism ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Dihydroxyvitamin D3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

We have investigated the molecular mechanism whereby 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits adipogenesis in vitro. 1,25(OH)2D3 blocks 3T3-L1 cell differentiation into adipocytes in a dose-dependent manner; however, the inhibition is ineffective 24–48 h after the differentiation is initiated, suggesting that 1,25(OH)2D3 inhibits only the early events of the adipogenic program. Treatment of 3T3-L1 cells with 1,25(OH)2D3 does not block the mitotic clonal expansion or C/EBPβ induction; rather, 1,25(OH)2D3 blocks the expression of C/EBPα, peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1, and other downstream adipocyte markers. The inhibition by 1,25(OH)2D3 is reversible, since removal of 1,25(OH)2D3 from the medium restores the adipogenic process with only a temporal delay. Interestingly, although the vitamin D receptor (VDR) protein is barely detectable in 3T3-L1 preadipocytes, its levels are dramatically increased during the early phase of adipogenesis, peaking at 4–8 h and subsiding afterward throughout the rest of the differentiation program; 1,25(OH)2D3 treatment appears to stabilize the VDR protein levels. Consistently, adenovirus-mediated overexpression of human (h) VDR in 3T3-L1 cells completely blocks the adipogenic program, confirming that VDR is inhibitory. Inhibition of adipocyte differentiation by 1,25(OH)2D3 is ameliorated by troglitazone, a specific PPARγ antagonist; conversely, hVDR partially suppresses the transacting activity of PPARγ but not of C/EBPβ or C/EBPα. Moreover, 1,25(OH)2D3 markedly suppresses C/EBPα and PPARγ mRNA levels in mouse epididymal fat tissue culture. Taken together, these data indicate that the blockade of 3T3-L1 cell differentiation by 1,25(OH)2D3 occurs at the postclonal expansion stages and involves direct suppression of C/EBPα and PPARγ upregulation, antagonization of PPARγ activity, and stabilization of the inhibitory VDR protein.

scholarly journals PPAR-γAgonist Alleviates Liver and Spleen Pathology via Inducing Treg Cells duringSchistosoma japonicumInfection

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yuxiao Zhu ◽  
Yangyue Ni ◽  
Ran Liu ◽  
Min Hou ◽  
Bingya Yang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Schistosoma Japonicum ◽  
Cellular Proliferation ◽  
Inflammatory Responses ◽  
Treg Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tissue Samples

Background. Peroxisome proliferator-activated receptor- (PPAR-)γplays critical roles in human metabolic disorders and has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Regulatory T cells (Tregs), which express high levels of PPAR-γprotein, have the ability to maintain immune tolerance to self-antigens and regulate immune response toSchistosomainfection. However, mechanisms involved in the resolution of these responses are elusive.Methods. Liver and spleen tissue samples inSchistosoma japonicum-infected mice after administration of pioglitazone (a PPAR-γagonist) were collected. The hepatic and splenic pathologies were detected by H&E and Masson staining. The percentages of Th1/2 and Treg cells in the liver and spleen of each mouse were determined using flow cytometry. Levels of gene expression of PPAR-γand Foxp3 in tissues or cells were determined using real-time PCR (RT-PCR). Macrophages were treated with pioglitazonein vitroor cocultured with normal purified CD4+T cells for detecting Treg cells by flow cytometry. The interactions of PPAR-γwith Foxp3 in CD4+T cells were detected by coimmunoprecipitation.Results. Administration of pioglitazone resulted in the prevention of the development of hepatic and splenic pathologies. Activation of PPAR-γby pioglitazone resulted in increased percentages of CD4+CD25+Foxp3+Treg cells and decreased percentages of CD3+CD4+IFN-γ+and CD3+CD4+IL-4+cells in the liver and spleen ofSchistosoma japonicum-infected mice. In addition, the PPAR-γagonist can induce Treg cellsin vitrodirectly or by modulating the macrophage’s function indirectly. Furthermore, through interaction with Foxp3 in CD4+T cells, the PPAR-γagonist can promote the expression of Foxp3; however, the inhibitor of PPAR-γweakened the expression of Foxp3 by modifying the coexpression of Foxp3 and PPAR-γ.Conclusions. Our study reveals a previously unrecognized role for PPAR-γ/Foxp3 signaling in regulating the immunopathology that occurs duringSchistosomainfection through induction of Treg cells.

scholarly journals Neuronal GPR30 Participates in Genistein-Mediated Neuroprotection in Ischemic Stroke by Inhibiting NLRP3 Inflammasome Activation in Ovariectomized Female Mice

2021 ◽  
Author(s):  
Shiquan Wang ◽  
Zhen Zhang ◽  
Jin Wang ◽  
Lina Ma ◽  
Jianshuai Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nlrp3 Inflammasome Activation

Abstract Estrogen replacement therapy (ERT) is potentially beneficial for the prevention and treatment of postmenopausal cerebral ischemia but inevitably increases the risk of cerebral hemorrhage and breast cancer when used for a long period of time. Genistein, a natural phytoestrogen, has been reported to contribute to the recovery of postmenopausal ischemic stroke with reduced risks. However, the underlying mechanism of genistein-mediated neuroprotection remains unclear. We reported that genistein exerted significant neuroprotective effects by enhancing the expression of neuronal G protein-coupled receptor 30 (GPR30) in the ischemic penumbra after cerebral reperfusion in ovariectomized (OVX) mice, and this effect was achieved through GPR30-mediated inhibition of nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we found that Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) was the pivotal molecule that participated in GPR30-mediated inhibition of NLRP3 inflammasome activation in OVX mice after ischemia/reperfusion (I/R) injury. Our data suggest that the neuronal GPR30/PGC-1α pathway plays an important role in genistein-mediated neuroprotection against I/R injury in OVX mice.

scholarly journals Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers

2002 ◽  
Vol 366 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Loretto H. PUCKEY ◽  
Brian L. KNIGHT
Keyword(s):  
Oestrogen Receptor ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apolipoprotein A ◽  
Increased Risk

A high plasma concentration of lipoprotein(a) [Lp(a)] confers an increased risk for the development of coronary heart disease. Hormones, such as oestrogen, are some of the few compounds known to reduce plasma Lp(a) levels. A putative enhancer region, located at the DHII DNase I hypersensitive site approx. 28kb upstream of the apolipoprotein(a) [apo(a)] gene, contains a number of sequences similar to the binding half-sites for nuclear hormone receptors, such as the oestrogen receptor and the peroxisome proliferator-activated receptor (PPAR). The 180bp core DHII enhancer increased the activity of the apo(a) promoter by over 7-fold in reporter-gene assays in HepG2 cells in vitro. Almost 60% of this increase was lost in the presence of co-transfected oestrogen receptor and oestrogen. In contrast, co-transfection with PPARα increased the effect of the DHII enhancer on apo(a) transcriptional activity by approx. 70% and could overcome the inhibitory effect of the oestrogen receptor on apo(a) transcription. Gel mobility-shift assays showed that oestrogen receptor protein bound to one half of a sequence corresponding to a predicted oestrogen receptor response element. PPARα also bound to this site and competed with oestrogen receptors for binding. In addition, PPARα bound to a separate site that comprised part of a direct repeat of nuclear hormone receptor half-sites. The results suggest that nuclear hormones affect plasma Lp(a) concentrations by binding to the sequences within the DHII enhancer, thereby altering the amount by which the enhancer increases the transcription of the apo(a) gene.

scholarly journals Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenyuan Ma ◽  
Zhengquan Huang ◽  
Li Zhang ◽  
Xiaochen Li ◽  
Bo Xu ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Vanillic Acid ◽  
Nlrp3 Inflammasome ◽  
Animal Experiments ◽  
Herbal Medicines ◽  
Receptor Protein ◽  
Caspase 1 ◽  
Monosodium Iodoacetate

Objectives: Synovitis plays an important role in knee osteoarthritis (KOA) pain. The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in fibroblast-like synoviocytes (FLSs) promotes KOA development. In this study, we aimed to investigate whether vanillic acid (VA), a monomer derived from Chinese herbal medicines, could target NLRP3 inflammasome-related synovitis to reduce pain.Methods: Rats in the KOA and KOA + VA groups were injected with monosodium iodoacetate (MIA) in the knee to induce KOA. From day 14, the KOA + VA group was given VA at 30 mg/kg every day via gastric intubation. FLSs were collected from the synovial tissues. We examined both the protein and gene expression of caspase-1, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), NLRP3, components of the NLRP3 inflammasome, and interleukin-1β (IL-1β) and IL-18 in vivo and in vitro.Results: The upregulation of caspase-1, ASC, and NLRP3 in the KOA model were reduced by VA. VA also lowered the level of IL-1β and IL-18 in the KOA model. In addition, VA relieved pain-related behavior of KOA model rats and downregulated the pain mediators CGRP, NGF, and TrkA in FLSs. Interestingly, we also observed reduced synovial fibrosis in the animal experiments.Conclusion: Our research showed that VA reduces synovitis and pain-related behaviors in a rat model of KOA, which provides the basis for further investigations into the potential therapeutic impact of VA in KOA.

scholarly journals Loss of Ron receptor signaling leads to reduced obesity, diabetic phenotypes and hepatic steatosis in response to high-fat diet in mice

2015 ◽  
Vol 308 (7) ◽  
pp. E562-E572 ◽  
Author(s):  
William D. Stuart ◽  
Nicholas E. Brown ◽  
Andrew M. Paluch ◽  
Susan E. Waltz
Keyword(s):  
Tyrosine Kinase ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ron Receptor ◽  
Membrane Spanning

The Ron receptor tyrosine kinase is a heterodimeric, membrane-spanning glycoprotein that participates in divergent processes, including proliferation, motility, and modulation of inflammatory responses. We observed male C57BL/6 mice with a global deletion of the Ron tyrosine kinase signaling domain (TK−/−) to be leaner compared with control (TK+/+) mice under a standard diet. When fed a high-fat diet (HFD), TK−/− mice gained 50% less weight and were more insulin sensitive and glucose tolerant than controls. Livers from HFD TK−/− mice were considerably less steatotic and weighed significantly less than TK+/+ livers. Serum cytokine levels of HFD TK−/− mice were also significantly altered compared with TK+/+ mice. Fewer and smaller adipocytes were present in the TK−/− mice on both control and HFD and were accompanied by diminished adiponectin and peroxisome proliferator-activated receptor-γ expression. In vitro adipogenesis experiments suggested reduced differentiation in TK−/− embryonic fibroblasts (MEFs) that was rescued by Ron reconstitution. Likewise, signal transducer and activator of transcription (STAT)-3 phosphorylation was diminished in TK−/− MEFs but was increased after Ron reconstitution. The adipogenic inhibitors, preadipocyte factor 1 and Sox9, were elevated in TK−/− MEFs and increased in both groups after STAT3 silencing. In total, these studies document a previously unknown function for the Ron receptor in mediating HFD-induced obesity and metabolic dysregulation.

NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity

2019 ◽  
Vol 75 (8) ◽  
pp. 1457-1464 ◽  
Author(s):  
Fabiola Marín-Aguilar ◽  
Beatriz Castejón-Vega ◽  
Elísabet Alcocer-Gómez ◽  
Debora Lendines-Cordero ◽  
Matthew A Cooper ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Nlrp3 Inflammasome ◽  
Mammalian Target Of Rapamycin ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aged Mice ◽  
Age Related

Abstract The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.

Sign in / Sign up

Export Citation Format

Share Document