The enhancement of TXA2 receptors-mediated contractile response in intrarenal artery dysfunction in type 2 diabetic mice.

Su-Juan Kuang, Jie-Sheng Qian, Hui Yang, Fang Rao, Xiao-Yan Chen, Meng-Zhen Zhang, Zhi-Xin Shan, Qiu-Xiong Lin, Yu-Mei Xue, Shu-Lin Wu, Li Jiang, Chun-Bo Chen, Chun-Yu Deng

European journal of pharmacology 2017 Jun 15

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Thromboxane A2 (TXA2) has been implicated in the pathogenesis of diabetic vascular complications, although the underlying mechanism remains unclear. The present study investigated the alterations in TXA2 receptor signal transduction in type 2 diabetic renal arteries. The contraction of renal arterial rings in control (db/m+) mice and type 2 diabetic (db/db) mice was measured by a Multi Myograph System. Intracellular calcium concentration ([Ca2+]i) in vascular smooth muscle cells was measured by Fluo-4/AM dye and confocal laser scanning microscopy. Quantitative real-time PCR and Western blot analysis were used to determine gene and protein expression levels, respectively. A stable TXA2 mimic U46619 caused markedly stronger dose-dependent contractions in the renal arteries of db/db mice than in those of db/m+ mice. This response was completely blocked by a TXA2 receptor antagonist GR32191 and significantly inhibited by U73122. U46619-induced vasoconstriction was increased in the presence of nifedipine in db/db mice compared with that in db/m+ mice, whereas the response to U46619 did not differ between the two groups in the presence of SKF96365. Sarcoplasmic reticulum Ca2+ release-mediated and CaCl2-induced contractions did not differ between the two groups. In db/db mice, store-operated Ca2+(SOC) entry-mediated contraction in the renal arteries and SOC entry-mediated Ca2+ influx in smooth muscle cells were significantly increased. And the gene and protein expressions of TXA2 receptors, Orai1 and Stim1 were upregulated in the diabetic renal arteries. Therefore the enhancement of U46619-induced contraction was mediated by the upregulation of TXA2 receptors and downstream signaling in the diabetic renal arteries. Copyright © 2017 Elsevier B.V. All rights reserved.

Citation

Su-Juan Kuang, Jie-Sheng Qian, Hui Yang, Fang Rao, Xiao-Yan Chen, Meng-Zhen Zhang, Zhi-Xin Shan, Qiu-Xiong Lin, Yu-Mei Xue, Shu-Lin Wu, Li Jiang, Chun-Bo Chen, Chun-Yu Deng. The enhancement of TXA2 receptors-mediated contractile response in intrarenal artery dysfunction in type 2 diabetic mice. European journal of pharmacology. 2017 Jun 15;805:93-100