High levels of uric acid upregulate endothelin receptors: the role of MAPK pathways in an in vitro study.

Introduction: Uric acid (UA) is the end product of the metabolism of purine compounds. There is overwhelming evidence linking hyperuricaemia (high levels of UA) and cerebrovascular diseases, but the effect of high levels of UA on cerebral vessels is not fully understood. The aim of this research is to clarify how UA affects the endothelin (ET) receptor in rat cerebral arteries and the related mechanism.

Material and methods: In an in vitro setting, segments of rat cerebral arteries (n = 12) were exposed to high levels of UA, either alone or in conjunction with MAPK pathway inhibitors. ET agonists were used to induce contractions that were then measured with a myograph. ET receptor expression was measured using RT-PCR (n = 6), western blot (n = 3), or immunohistochemistry (n = 3) to quantify mRNA and protein levels.

Results: The study revealed that high levels of UA notably increase ET_A and ET_B receptor-induced contractions and boosted the expression of ET receptors in cerebral arteries when compared to fresh or cultured alone, suggesting that UA enhances ET_A and ET_B receptors. Additionally, the up-regulation of ET_B receptors induced by UA was inhibited by the p38 inhibitor SB203580, the JNK inhibitor SP600125, and the ERK1/2 inhibitor U0126. SB203580 significantly blocked the increase in ET_A receptor-mediated contractions induced by UA and the upregulation of ET_A receptor. Neither SP600125 nor U0126 had such an effect.

Conclusions: High levels of UA stimulate the up-regulation of ET receptors in rat cerebral arteries in vitro through MAPK pathways. This study may offer novel perspectives on hyperuricaemia-associated cerebrovascular diseases.