Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways.

Abstract Hypertension is one of the most frequent complications of solid organ transplantation, and cyclosporin A (CsA) plays a predominant role in the pathophysiology of post-transplant hypertension. However, the exact molecular mechanisms of CsA-induced hypertension remain obscure. We previously showed that CsA increased the mRNA expression and contractile function of endothelin B (ET B ) receptor in vascular smooth muscle cells. The present study was designed to investigate the underlying mechanisms of CsA-induced upregulation of ET B receptor in vasculature. Rat mesenteric arteries were incubated with CsA in an organ culture system, and results showed that CsA enhanced ET B receptor mRNA in the time- and dose-dependent manner, and increased protein expression levels of ET B receptor after treatment with CsA 10 −5  M for 6 h. Furthermore, CsA induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), p38, and translocation of nuclear factor-kappaB (NF-κB) p65 in vasculature. Blocking ERK1/2, p38, or NF-κB activation with their specific inhibitors markedly attenuated CsA-induced upregulation of ET B receptor mRNA expression and protein levels, and ET B receptor-mediated contraction. In summary, this study showed that mitogen-activating protein kinases (ERK1/2 and p38) and the downstream transcriptional factor NF-κB pathways were involved in CsA-induced upregulation of ET B receptor in arterial smooth muscle cells.