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Basic Clin Pharmacol Toxicol. 2010 Oct;107(4):803-12. doi: 10.1111/j.1742-7843.2010.00585.x.

Up-regulation of G-protein-coupled receptors for endothelin and thromboxane by lipid-soluble smoke particles in renal artery of rat.

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1
Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.

Abstract

Up-regulation of G-protein-coupled receptors (GPCR) plays key roles in renal hypertension and cardiovascular disease pathogenesis. The present study was designed to examine if lipid-soluble cigarette smoking particles (DSP), nicotine and endotoxin (LPS), induce GPCR up-regulation for thromboxane A(2) (TP), endothelin type A (ET(A) ) and type B (ET(B) ) receptors in renal artery, and if intracellular signal mechanisms are involved. Renal artery segments of rats were exposed to DSP, nicotine or LPS, in organ culture for up to 24 hr. The GPCR-mediated contractions were recorded by using a myograph system. Expression of the GPCR was examined by real-time PCR and immunohistochemistry at mRNA and protein levels. Sarafatoxin 6c (S6c, selective ET(B) receptor agonist), endothelin-1 (ET-1, non-selective ET(A) and ET(B) receptor agonist) and 9,11-Dideoxy-9a,11a-methanoepoxy prostaglandin F(2a) (U46619, a TP receptor agonist) induced contractions were significantly increased after the arterial segments exposed to DSP in a concentration-dependent (0.1-0.4 μl/ml) manner, and S6c also induced a time-dependent contraction, compared to control (dimethyl sulfoxide). This was in parallel with enhanced mRNA expression for ET(B) receptor but not ET(A) and TP receptors, while increased protein expression for ET(A) , ET(B) and TP receptors was seen. The specific nuclear factor-kappa B (NF-κB) signal pathway inhibitor BMS345541 was applied to link DSP effects to the GPCR up-regulation. It totally abolished ET(B) receptor up-regulation, but not ET(A) and TP receptor up-regulations. Our results suggest that DSP transcriptionally up-regulated ET(B) receptor expression in rat renal artery via NF-κB signal pathways, whereas up-regulation of ET(A) and TP receptor-mediated contraction may involve post-transcriptional mechanisms.

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