Abstract: FR-PO407
Increased Epithelial Sodium Channel (ENaC) Activity Mediates Fructose-Induced Salt-Sensitive Hypertension
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Zhang, Ronghao, Case Western Reserve University, Cleveland, Ohio, United States
- Shi, Shujie, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Kleyman, Thomas R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Gonzalez-Vicente, Agustin, Case Western Reserve University, Cleveland, Ohio, United States
Background
Elevated dietary fructose causes sodium retention and salt-sensitive hypertension. In a preliminary bioinformatics study on kidney cortexes from fructose-fed rats, we found an increase in aldosterone-responsive genes, which included subunits of the Epithelial Sodium Chanel (ENaC). Regulation of ENaC in the aldosterone sensitive distal tubule involves transcriptional and post-translational mechanisms, and is key to maintain electrolyte homeostasis and blood pressure. An important post-translational regulation of α-ENaC and γ-ENaC subunits is cleavage activation by luminal and intracellular proteases. We hypothesized that “dietary fructose increases ENaC subunits expression and cleavage, thereby contributing to sodium retention and salt-sensitive hypertension”.
Methods
Sprague-Dawley rats were fed with matched diets containing 4% NaCl and either 20% fructose (FHS) or glucose (GHS) for up to 11 days. Protein expression and RNA transcripts abundance were measured in the kidney cortex by Western blotting and next generation sequencing, respectively. The expression of cleaved α-ENaC and γ-ENaC subunits was measured as surrogate of ENaC activation. The effect of inhibiting ENaC on blood pressure was assessed by tail-cuff plethysmography on rats given oral amiloride for 24h.
Results
Seven days after starting the diets, FHS presented higher abundance of both α-ENaC transcripts (Scnn1a gene; log2FC = 1.04; p = 0.01, n = 6) and proteins (121±20 vs. 64±10 normalized optical density (OD); Δ 90±34 %, p < 0.03, n = 6) as compared to GHS. No differences in either protein or RNA abundance were found for γ-ENaC or β-ENaC subunits. In addition, the expression of cleaved α-ENaC protein, was higher in FHS than in GHS (85±8 vs. 58±5 OD; Δ 48±16 %, p < 0.01, n = 6). Between days 5 and 10 of dietary intervention, FHS showed significantly higher systolic pressures than GHS (144±5 vs. 127±4 mmHg; Δ17±4 mmHg, p < 0.03, n=6). Oral amiloride from days 10 to 11 reduced systolic pressure in FHS by 10±4 mmHg (paired t-test: p ≤ 0.05), while caused no significant change in GHS (paired t-test: p = 0.23).
Conclusion
Rats consuming a diet rich in fructose and sodium, present increased expression and activity of ENaC than those eating a diet matched with glucose, contributing to the salt-sensitivity of blood pressure seen in this model.
Funding
- NIDDK Support