TAK-242, a Toll-Like Receptor 4 Antagonist, Protects against Aldosterone-Induced Cardiac and Renal Injury

Zhang, Yide; Peng, Weilin; Ao, Xiang; Dai, Houyong; Li, Yuan; Huang, Xinzhong; Zhou, Qiaoling

doi:10.1371/journal.pone.0142456

Cited by 47 publications

(41 citation statements)

References 50 publications

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“…In a spinal cord compression injury model, Sprague–Dawley rats were treated with intraperitoneal TAK-242 (TLR4 antagonist), which reduced pain at low doses (Zhang et al. 2015 ; Zhao et al. 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

Jurga

Rojewska

Makuch

et al. 2018

Pharmaceutical Biology

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Context: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception.Objective: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed.Materials and methods: Behavioural (von Frey’s/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 μG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7.Results: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy.Conclusions: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

Jurga

Rojewska

Makuch

et al. 2018

Pharmaceutical Biology

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“…A suspension of microspheres in saline solution containing about 3000 microspheres (42 µm in diameter, Biosphere Medical Inc. Rockland, USA) was injected into the LV during 10s occlusion of the ascending aorta. Rats in the CME plus TAK-242 group received an intravenous injection of TAK-242 (2 mg/kg, MedChem Express, Princeton, USA) via the tail vein 30min before surgery [21], and rats in the sham group received an injection of the same volume of normal saline only.…”

Section: Methodsmentioning

confidence: 99%

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

Wang¹,

Lu²,

Sun³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Myocardial apoptosis is heavily implicated in the myocardial injury caused by coronary microembolization (CME), and toll-like receptor 4 (TLR4) is considered to be involved in this apoptotic cascade. Therefore, the present study was designed to investigate the role of TLR4/NF-κB signaling pathway regulated by TAK-242, a selective TLR4 signal transduction inhibitor, in the myocardial apoptosis after CME in rats. Methods: Forty-five rats were randomized (random number) into three groups: sham, CME and CME + TAK-242 (n = 15 per group).CME was induced by injecting polyethylene microspheres (42µm) into the left ventricular except the sham group. CME + TAK-242 group was treated with TAK-242 (2mg/kg) via the tail vein 30 minutes before CME modeling. Cardiac function was evaluated 6 hours after operation. Tissue biopsy was stained with HBFP to measure the size of micro-infarction area. TUNEL staining was used to detect myocardial apoptosis. Western blot and qPCR were used to evaluate the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3. Results: Cardiac function in the CME group and CME + TAK-242 group were significantly decreased compared with the sham group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, NF-κB p65, p-IκBα and Cleaved caspase-3 were increased significantly (P < 0.05). Cardiac function in the CME + TAK-242 group was significantly improved compared with the CME group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3 were decreased significantly (P < 0.05). Conclusions: TAK-242 can effectively improve CME-induced cardiac dysfunction by regulating TLR4/NF-κB signaling pathway and then reducing the myocardial apoptosis.

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“…Previous studies demonstrated that inflammation plays an important role in the pathogenesis of hypertension, and the development and progression of renal fibrosis. 13,36,37 We then assayed the expression of various proinflammatory cytokines by qPCR and ELISA. Figure 1C-F showed that the cardiac mRNA and protein levels of TNF-a, MCP-1, and IL-1β are markedly increased by Aldo infusion, whereas SB-216763 treatment inhibits cardiac inflammatory cytokines levels ( Figure 1C-F).…”

Section: Sb-216763 Suppresses Aldo-induced Cardiorenal Inflammationmentioning

confidence: 99%

SB‐216763, a GSK‐3β inhibitor, protects against aldosterone‐induced cardiac, and renal injury by activating autophagy

Zhang

Ding

Dai

et al. 2018

J of Cellular Biochemistry

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Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays a pivotal role in the pathogenesis of hypertension and renal fibrosis. GSK‐3β contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo‐induced hypertension, and renal damage is not clear. In the present study, rats were treated with Aldo combined with SB‐216763 (a GSK‐3β inhibitor) for 4 weeks. Hemodynamic, cardiac, and renal parameters were assayed at the indicated time. Here we found that rats treated with Aldo presented cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of molecular markers attesting inflammation and fibrosis were increased by Aldo infusion, whereas the treatment of SB‐216763 reversed these alterations. SB‐216763 suppressed cardiac and renal inflammatory cytokines levels (TNF‐a, IL‐1β, and MCP‐1). Meanwhile, SB‐216763 increased the protein levels of LC3‐II in the cardiorenal tissues as well as p62 degradation, indicating that SB‐216763 induced autophagy activation in cardiac, and renal tissues. Importantly, inhibition of autophagy by 3‐MA attenuated the role of SB‐216763 in inhibiting perivascular fibrosis, and tubulointerstitial injury. These data suggest that SB‐216763 protected against Aldo‐induced cardiac and renal injury by activating autophagy, and might be a therapeutic option for salt‐sensitive hypertension and renal fibrosis.

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TAK-242, a Toll-Like Receptor 4 Antagonist, Protects against Aldosterone-Induced Cardiac and Renal Injury

Cited by 47 publications

References 50 publications

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

SB‐216763, a GSK‐3β inhibitor, protects against aldosterone‐induced cardiac, and renal injury by activating autophagy

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