Downregulation of Thromboxane A2 Receptor Occurs Mainly via Nuclear Factor-KappaB Signaling Pathway in Rat Renal Artery.

Yaping Zhang,Cang-Bao Xu,Man Mi,Si-Wang Wang,Yan-Hua Xie,Lars Edvinsson

doi:10.1155/2017/6507048

Abstract

Thromboxane A2 (TXA2) acts on TXA2 receptors (TP) to regulate renal artery blood flow and subsequently contributes to the pathogenesis of renal ischemia. The present study was designed to examine if nuclear factor-kappaB (NF-κB) signaling pathway is involved in the downregulation of TP receptors in rat renal artery. Rat renal artery segments were organ cultured for 6 or 24 h. Downregulation of TP receptors was monitored using myograph (contractile function), real-time PCR (receptor mRNA), and immunohistochemistry (receptor protein). Specific inhibitors (MG-132 and BMS345541) for NF-κB signaling pathway were used to dissect the underlying molecular mechanisms involved. Compared to fresh (noncultured) segments, organ culture of the renal artery segments for 24 h induced a significant rightward shift of U46619 (TP receptor agonist) contractile response curves (pEC50: 6.89 ± 0.06 versus 6.48 ± 0.04, P < 0.001). This decreased contractile response to U46619 was paralleled with decreased TP receptor mRNA and protein expressions in the renal artery smooth muscle cells. Specific inhibitors (MG-132 and BMS345541) for NF-κB signaling pathway significantly abolished the decreased TP protein expression and receptor-mediated contractions. In conclusion, downregulation of TP receptors in the renal artery smooth muscle cells occurs mainly via the NF-κB signaling pathway.

Highlights

Thromboxane A2 (TXA2) is mainly derived from platelets and vascular endothelial cells
Surgical reduction of renal mass in TXA2 receptor (TP) receptor knockout (TP-R−/−) mice demonstrated that activation of TP receptors mediated the increase in endothelin-1 (ET-1), reactive oxygen species (ROS), and microvascular remodeling and enhanced contractions in microvessels in chronic kidney disease [7], suggesting that TXA2 and its receptors were involved in the development of acute and chronic kidney injury
To study TP receptor mRNA expression and the receptor-mediated contractions, rat renal artery ring segments were cultured in the serum-free culture medium for 6 or 24 h

Summary

Introduction

Thromboxane A2 (TXA2) is mainly derived from platelets and vascular endothelial cells It acts on TXA2 receptor (TP) to induce strong vasoconstriction in renal arteries [1, 2]. In mice with cell-specific deletion of TP receptors in vascular smooth muscle cells, TP receptor agonist U46619 failed to induce shock and hypertension, and angiotensin II-induced hypertension, vascular remodeling, and urinary thromboxane production were all significantly attenuated [5]. This indicated that TP receptors play a central role in the pathogenesis of these diseases. Surgical reduction of renal mass in TP receptor knockout (TP-R−/−) mice demonstrated that activation of TP receptors mediated the increase in endothelin-1 (ET-1), reactive oxygen species (ROS), and microvascular remodeling and enhanced contractions in microvessels in chronic kidney disease [7], suggesting that TXA2 and its receptors were involved in the development of acute and chronic kidney injury

Results

Discussion

Conclusion