CFTR plays an important role in the regulation of vascular resistance and high-fructose/salt-diet induced hypertension in mice

Abstract

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 ( cf tr + / + ) FVB and CFTR -knockout ( cf tr −/ − ) 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.

CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca𝟐+ influx and RhoA/Rock pathway in VSMCs

“…In previous study, average SBP and DBP of 24hour, daytime and night time of Cftr −/− mice were all significantly higher than those of Cftr +/+ mice, however, Cftr knockout did not alter SBP or DBP recorded from 4:00 PM to 8:00 PM [12]. To investigate whether CFTR play a part in Ang II induced hypertension, Cftr +/+ and Cftr −/− mice were used to establish Ang II infusion induced hypertension model, SBP and DBP was measured at 6:00 PM 0, 3, 6, 9, 12 and 14 days after the pumps were implanted.…”

“…Moreover, Cftr knockout enhanced Ang II induced BP elevation during the development of hypertension, without altering BP in normotensive mice. Previous study indicated that CFTR might play a little role in circadian regulation of BP [12]. Both Cftr −/− and Cftr +/+ mice displayed a bimodal circadian pattern over 24-hour period but BP peaks of Cftr −/− mice were higher and later when compared to Cftr +/+ mice.…”

“…Older female CF mutation (not gene deletion) carriers showed lower BP than matched control subjects [11] and F508del heterozygous mice had lower arterial pressures than wild-type mice [35], which had been attributed to excessive salt depletion. Ya-Ping Zhang et al [12] demonstrated that 24-hour average physiological SBP and DBP of Cftr −/− mice were all significantly higher than those of Cftr +/+ mice.…”

“…Clinical data showed that older female CF mutation carriers exhibited lower blood pressure (BP), which had been attributed to excessive salt depletion [11]. Radiotelemetry measurements of physiological blood pressure demonstrated that average SBP and DBP of 24-hour of Cftr −/− mice were all significantly higher than those of Cftr +/+ mice [12]. These previous studies indicated that CFTR might play an important role in BP control, however, the regulating effect of CFTR on the genesis of hypertension remains unclear.…”

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

“…CFTR (CF transmembrane conductance regulator) [380], RHOB (ras homolog family member B) [396], LMNA (lamin A/C) [388], HGF (hepatocyte growth factor) [371], CCL5 [360] and NGFR (nerve growth factor receptor) [383] were altered expression in the Alzheimer’s Disease. CFTR (CF transmembrane conductance regulator) [551], LMNA (lamin A/C) [558], ERBB3 [331], HGF (hepatocyte growth factor) [494], CCL5 [540] and NGFR (nerve growth factor receptor) [554] have been demonstrated to accelerate hypertension progression. LMNA (lamin A/C) [222], HGF (hepatocyte growth factor) [212] and NGFR (nerve growth factor receptor) [220] expression migh be regarded as an indicator of susceptibility of amyotrophic lateral sclerosis.…”