BACKGROUND The pathophysiological roles of cystic fibrosis transmembrane-conductance regulator (CFTR) Cl- channels in the regulation of blood pressure (BP) remain controversial. Here we studied the function of CFTR Cl- channels in regulation of BP and in the high-fructose-salt-diet (HFSD) induced hypertension in mice. METHODS The systolic, diastolic and mean BP (SBP, DBP and MBP, respectively) were continuously monitored from unrestricted conscious wild-type (cftr+/+) FVB and CFTR-knockout (cftr-/-) mice (8-week old, male). HFSD (64.7% fructose, 2% NaCl water) or control normal starch diet (CNSD, 58.9% corn starch, 0 NaCl water) was given for 8 weeks and vascular Doppler were performed. Real-time PCR and Western blot were used to examine mRNA and protein expression, respectively. RESULTS The aortic stiffness, daytime and nighttime SBP, DBP, and MBP of the cftr-/- mice were significantly higher than those in the age- and gender-matched cftr+/+ mice, which is consistent with the findings of increased vascular resistance in cystic fibrosis patients. The aortic stiffness, daytime and nighttime SBP, DBP, and MBP of cftr+/+ mice fed with HFSD were all significantly higher than those fed with CNSD. Importantly, HFSD caused a significant decrease in mRNA and protein expression of WINK1, WINK4 and CFTR in aorta and mesenteric arteries, but not in the kidney, corroborating that HSFD-induced downregulation of WINKs and loss of CFTR function specifically in the arteries may mediate the increased BP. CONCLUSIONS CFTR regulates peripheral arterial resistance and BP in vivo. HFSD-induced CFTR downregulation specifically in the arteries may be a novel mechanism for hypertension.

中文翻译：

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CFTR在调节小鼠血管阻力和高果糖/盐饮食诱导的高血压中起重要作用

背景 囊性纤维化跨膜电导调节剂 (CFTR) Cl-通道在调节血压 (BP) 中的病理生理作用仍存在争议。在这里，我们研究了 CFTR Cl-通道在调节 BP 和高果糖盐饮食 (HFSD) 诱导的小鼠高血压中的功能。方法 连续监测不受限制的有意识野生型 (cftr+/+) FVB 和 CFTR 基因敲除 (cftr-/-) 小鼠（8 周龄，雄性）的收缩压、舒张压和平均 BP（分别为 SBP、DBP 和 MBP） ）。HFSD（64.7% 果糖，2% NaCl 水）或对照普通淀粉饮食（CNSD，58.9% 玉米淀粉，0 NaCl 水）持续 8 周并进行血管多普勒检查。实时荧光定量 PCR 和蛋白质印迹分别用于检查 mRNA 和蛋白质表达。结果 主动脉僵硬度、白天和夜间 SBP、DBP、cftr-/- 小鼠的 MBP 和 MBP 显着高于年龄和性别匹配的 cftr+/+ 小鼠，这与囊性纤维化患者血管阻力增加的发现一致。喂食 HFSD 的 cftr+/+ 小鼠的主动脉僵硬度、白天和夜间 SBP、DBP 和 MBP 均显着高于喂食 CNSD 的那些。重要的是，HFSD 导致主动脉和肠系膜动脉中 WINK1、WINK4 和 CFTR 的 mRNA 和蛋白质表达显着降低，但在肾脏中没有，这证实了 HSFD 诱导的 WINK 下调和动脉中特异性 CFTR 功能的丧失可能介导血压升高。结论 CFTR 在体内调节外周动脉阻力和血压。HFSD 诱导的动脉特异性 CFTR 下调可能是高血压的一种新机制。