Abstract 170: CFTR as a Novel Target and Mechanism for High-Fructose Diet and Salt-Induced Hypertension

Abstract

Objective: High fructose and salt diet (HFSD) consumption is very common in modern lifestyle. Fructose not only stimulates intestinal salt and water absorption but also decreases renal sodium (Na+) and chloride (Cl-) excretion. High fructose intake induces rapid and sustained increase in blood pressure (BP). But a Cl--free diet could block fructose-induced hypertension. The underlying mechanism for this Cl_dependence of high fructose and salt induced hypertension is not clear. This study was designed to test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel may play a critical role in the HFSD-induced hypertension. Approach and Results: The DSI HD-X11 transmitters for telemetry recordings of both blood pressure and ECG were implanted into CFTR-knockout (CFTR-/-) mice (8-week old, male) and their age- and gender-matched wild-type (CFTR+/+) mice. The systolic (SBP), diastolic (DBP) and mean BP (MBP) and ECG of the mice before and after feeding with HFSD (%65 fructose, 2% salt) were monitored daily for 8 weeks. Continuous 8-week HFSD caused a significant increase in aortic stiffness, mesenteric and renal artery resistance, SBP, DBP, and MBP in CFTR+/+ mice. Real-time PCR and Western blot analysis revealed a significant decrease (~90%) in CFTR mRNA and protein expression in aorta and mesenteric arteries but not in the heart and brain. This HFSD-induced specific down-regulation of CFTR was highly correlated with the HFSD-induced reduction in WINK1 and WINK4 expression in aorta and mesenteric artery. In the mice fed with normal diet the aortic stiffness, mesenteric and renal artery resistance and the SDP, DBP, and MBP at either daytime or nighttime was significantly higher in CFTR-/- mice (n=8) than in CFTR+/+ mice (n=15), implicating an important functional role for CFTR in the regulation of vascular resistance and BP. Conclusions: 1) CFTR plays a pivotal functional role in the regulation of arterial resistance and BP; 2) HFSD may cause hypertension through a specific WINKs-CFTR signaling pathway. These results provide compelling evidence that diet may cause changes in expression of specific genes in the vasculature and CFTR may represent a novel molecular target and mechanism for the HFSD-induced hypertension.