Up‐Regulation of G‐Protein‐Coupled Receptors for Endothelin and Thromboxane by Lipid‐Soluble Smoke Particles in Renal Artery of Rat

Xie, Youhua; Wang, Siwang; Zhang, Yaping; Edvinsson, Lars; Xu, Cang‐Bao

doi:10.1111/j.1742-7843.2010.00585.x

Cited by 13 publications

(9 citation statements)

References 41 publications

(48 reference statements)

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“…Increased renal artery contractility leads to increased renal vascular resistance and reduced renal blood flow, which is often seen in renal vasospasm , renal artery stenosis and endotoxaemic shock‐induced renal ischaemia . Previously, we have reported that rat renal artery segments exposed to smoke particles increase renal artery contractility through transcriptional and post‐transcriptional up‐regulation of contractile GPCRs for endothelin and thromboxane . The present study has demonstrated that organ culture of renal artery segments increases renal artery contractility via up‐regulation of both ET A and ET B2 receptors in the smooth muscle cells.…”

Section: Discussionsupporting

confidence: 50%

“…Previously, we have studied the effects of dimethylsulphoxide (DMSO)‐extracted smoke particles (DSP) on rat renal artery contractility. The results show that DSP transcriptionally up‐regulates ET B2 receptors with enhanced contraction in rat renal artery, whereas up‐regulation of ET A and thromboxane receptor‐mediated contraction may involve post‐transcriptional mechanisms . The present study demonstrates that organ culture induces increased renal artery contractility through transcriptional up‐regulation of both ET A and ET B2 receptors in the smooth muscle cells, and activation of NF‐κB‐mediated transcriptional mechanisms is involved in this process.…”

mentioning

confidence: 50%

“…This explains inconsistent results among the levels of the receptor mRNA and protein expressions and receptor‐mediated contraction, particularly the results obtained from the ET A receptor studies. Our previous studies suggest that up‐regulation of ET B2 receptor expression in the renal artery smooth muscle cells is mainly through a transcriptional mechanism, while the regulation of ET A receptor‐mediated contraction is most likely via non‐transcriptional mechanisms . More complex molecular mechanisms might be also involved in the regulation of endothelin receptor expression and functions, because of evidence demonstrating that in artery smooth muscle cells, there are ET A and ET B receptor cross‐talk and intracellular signalling cross‐talk as well .…”

Section: Discussionmentioning

confidence: 99%

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Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats

Xie

Wang

Zhang

et al. 2013

Basic Clin Pharma Tox

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Increased renal artery contractility leads to renal vasospasm and ischaemia as well as kidney damage. This study was designed to examine the hypothesis that organ culture of renal arteries induces transcriptional up-regulation of endothelin type A (ET A ) and type B2 (ET B2 ) receptors in the smooth muscle cells via activation of nuclear factor-kappaB (NF-jB) and subsequently increases renal artery contractility. Rat renal artery segments were organ-cultured for 6 or 24 hr to increase endothelin receptor-mediated contraction. To dissect molecular mechanisms involved in this process, inhibitors for NF-jB signalling pathway (MG-132 and BMS345541), transcription (actinomycin D) and translation (cycloheximide) were used during organ culture. Endothelin receptors were studied using a sensitive myograph (functional contractility), real-time PCR (mRNA analysis) and immunohistochemistry (protein localization). Compared with fresh segments, contractile responses to endothelin-1 (non-selective endothelin receptor agonist) and sarafotoxin 6c (selective ET B receptor agonist) were significantly increased in the segments after 24 hr of organ culture; ET B2 receptor-mediated maximal contraction increased from 2.7 AE 0.5 to 135.3 AE 5.1 (p < 0.001), and potency (pEC 50 ) of ET A receptor agonist increased from 8.20 AE 0.04 to 8.72 AE 0.07 (p < 0.001). This was in parallel with increased corresponding mRNA and protein expression for ET A and ET B2 receptors. BMS345541, MG-132, actinomycin D or cyclohexamide, respectively, suppressed the up-regulation of ET A and ET B2 receptors. Immunostaining performed with specific antibody showed that IjB was phosphorylated during organ culture. In conclusion, activation of NF-jB mediates up-regulation of ET A and ET B2 receptors and subsequently increases renal artery contractility, which may contribute to renal vasospasm and ischaemia as well as kidney damage.Increased renal vascular contractility and resistance trigger a cascade of events that lead to reduced renal blood flow, renal ischaemia and dysfunction, and even structural injury of kidney [1,2]. This cascade is often seen in endotoxaemic shockinduced renal ischaemia [3,4], renal artery stenosis [1] and severe renal artery spasm after blunt abdominal trauma [5], percutaneous transluminal renal angioplasty [6] and abdominal neuroblastoma removal [7]. However, the underlying molecular mechanisms that are responsible for the increased renal artery contractility and reduced renal blood flow are still not fully understood. Fenhammar et al. [4] reported that treatment with the dual endothelin receptor antagonist tezosentan in a porcine model of endotoxaemic shock attenuates the reduction of renal microcirculation and total renal blood flow, suggesting that endothelin-1 (ET-1) and its receptors are involved in the renal ischaemia. A recent study demonstrates that ET-1 released during endotoxaemia acts via endothelin type A (ET A ) receptors to impair renal blood flow and cause acute kidney injury [3]. To provide novel knowledge a...

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Section: Discussionsupporting

confidence: 50%

mentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

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Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats

Xie

Wang

Zhang

et al. 2013

Basic Clin Pharma Tox

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“…Landmark papers [2], [3] have demonstrated that COX-derived prostanoids (prostacyclin and thromboxane) significantly influence cardiovascular disease, with thromboxane promoting atherothrombotic events. Diabetes mellitus [4] , [5], smoking [6], [7], [8], and obesity [9], [10] (key cardiovascular risk factors) are associated with increased thromboxane levels. Low dose aspirin, a cyclooxygenase inhibitor (COX-1>> COX-2), reduces platelet thromboxane production leading to protective effects in women (against strokes) and men (myocardial events) [11].…”

Section: Introductionmentioning

confidence: 99%

Human Thromboxane A2 Receptor Genetic Variants: In Silico, In Vitro and “In Platelet” Analysis

et al. 2013

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Thromboxane and its receptor have emerged as key players in modulating vascular thrombotic events. Thus, a dysfunctional hTP genetic variant may protect against (hypoactivity) or promote (hyperactivity) vascular events, based upon its activity on platelets. After extensive in silico analysis, six hTP-α variants were selected (C68S, V80E, E94V, A160T, V176E, and V217I) for detailed biochemical studies based on structural proximity to key regions involved in receptor function and in silico predictions. Variant biochemical profiles ranged from severe instability (C68S) to normal (V217I), with most variants demonstrating functional alteration in binding, expression or activation (V80E, E94V, A160T, and V176E). In the absence of patient platelet samples, we developed and validated a novel megakaryocyte based system to evaluate human platelet function in the presence of detected dysfunctional genetic variants. Interestingly, variant V80E exhibited reduced platelet activation whereas A160T demonstrated platelet hyperactivity. This report provides the most comprehensive in silico, in vitro and “in platelet” evaluation of hTP variants to date and highlightscurrent inherent problems in evaluating genetic variants, with possible solutions. The study additionally provides clinical relevance to characterized dysfunctional hTP variants.

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“…Lipid-soluble smoke particles consisting of DMSO-soluble particles (DSP), nicotine, and lipopolysaccharides, upregulate G protein-coupled receptors for potent contractile agents, endothelin and thromboxane, [128] which contribute to endothelial dysfunction [129]. In addition to upregulating contractile receptors, LPS exposure simultaneously increases activation of inflammatory and contractile thromboxane and angiotensin I receptors while inhibiting anti-inflammatory and dilatory prostacyclin and acetylcholine receptors [130].…”

Section: Smoking and Oxidative Stressmentioning

confidence: 99%

An eicosanoid-centric view of atherothrombotic risk factors

Gleim

Stitham

Tang

et al. 2012

Cell. Mol. Life Sci.

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Up‐Regulation of G‐Protein‐Coupled Receptors for Endothelin and Thromboxane by Lipid‐Soluble Smoke Particles in Renal Artery of Rat

Cited by 13 publications

References 41 publications

Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats

Nuclear Factor‐kappaB‐Mediated Endothelin Receptor Up‐Regulation Increases Renal Artery Contractility in Rats

Human Thromboxane A2 Receptor Genetic Variants: In Silico, In Vitro and “In Platelet” Analysis

An eicosanoid-centric view of atherothrombotic risk factors

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