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

• Published in: European journal of pharmacology Vol. 805; pp. 93 - 100
• Main Authors: Kuang, Su-Juan, Qian, Jie-Sheng, Yang, Hui, Rao, Fang, Chen, Xiao-Yan, Zhang, Meng-Zhen, Shan, Zhi-Xin, Lin, Qiu-Xiong, Xue, Yu-Mei, Wu, Shu-Lin, Jiang, Li, Chen, Chun-Bo, Deng, Chun-Yu
• Format: Journal Article
• Language: English
• Published: Netherlands 15-06-2017
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Arteries - drug effects; Arteries - physiopathology; Calcium Channels - metabolism; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; Kidney - blood supply; Male; Mice; Mice, Inbred C57BL; Receptors, Thromboxane A2, Prostaglandin H2 - metabolism; Signal Transduction - drug effects; Vasoconstriction - drug effects; Ca(2+) channel; Diabetic mice; Renal artery; SOC entry; U46619; Vasoconstriction
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.03.006

Thromboxane A
(TXA
) has been implicated in the pathogenesis of diabetic vascular complications, although the underlying mechanism remains unclear. The present study investigated the alterations in TXA
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 ([Ca
]
) 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 TXA
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 TXA
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 Ca
release-mediated and CaCl
-induced contractions did not differ between the two groups. In db/db mice, store-operated Ca
(SOC) entry-mediated contraction in the renal arteries and SOC entry-mediated Ca
influx in smooth muscle cells were significantly increased. And the gene and protein expressions of TXA
receptors, Orai1 and Stim1 were upregulated in the diabetic renal arteries. Therefore the enhancement of U46619-induced contraction was mediated by the upregulation of TXA
receptors and downstream signaling in the diabetic renal arteries.