Abstract: PO2150
The Effect of Epidermal Growth Factor Inhibition on Salt Sensitivity in Mice
Session Information
- Mechanisms of Kidney and Vascular Disease
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- King, Keyona, Emory University School of Medicine, Atlanta, Georgia, United States
- Hoover, Robert S., Emory University School of Medicine, Atlanta, Georgia, United States
Background
Every year in the United States, more than 3 million adults are determined to have high blood pressure. Studies have shown that the epidermal growth factor (EGF) decreases the open probability of the epithelial-Na+ channel (ENaC) along the apical surface of the kidney cortical collecting duct (CCD). Yet, it is unknown whether EGF influences renal Na+ transport via the Na+-Cl- cotransporter (NCC). Our laboratory has investigated whether EGF regulates NCC. We performed various in vitro experiments using mouse distal convoluted (mDCT-15) cells and found that EGF decreases NCC surface expression with an increase in endocytosis of surface NCC. Overall, our findings and those from other researchers, collectively suggest that EGF decreases the activity of two key mediators of salt-sensitive blood pressure, ENaC and NCC. This discovery served as our rationale for investigating whether EGF inhibition affects BP, and if this response is related to dietary sodium intake.
Methods
Using radio-telemetry, we collected the systolic blood pressure (SBP) measurements in five male mice ages 7 weeks old. These animals received a low salt (LS) diet (0.4% Na chow) for 6 days and high salt (HS) diet (4% Na chow) for 8 days. Over a period of two weeks, only the experimental (E) group (n=3) received gefitinib (an EGF receptor tyrosine kinase inhibitor) at a regimen of 100 mg/kg/d given orally while the control (C) group (n=2) received a placebo.
Results
The results for the change in awake-SBP while receiving diet (0.4% Na chow) for 6 days and high salt (HS) diet (4% Na chow), showed the experimental (E) group had a greater increase in SBP in response to a higher dietary Na+ intake (E group: 7.70 ± 0.17 vs. control (C) group: 0.311 ± 0.29 mmHg, p<0.001). The delta for the difference in BP change when increasing the dietary Na+ intake was greater for the E group of mice (delta = 7.40 mmHg, p<0.001).
Conclusion
Therefore, our data strongly suggests that inhibition of EGF increases the salt sensitivity of blood pressure. This may indicate that EGFR ligands act as tonic inhibitors of tubular sodium reabsorption. Future experiments will explore the in vivo effects of EGFR inhibition on NCC, ENaC and sodium excretion.
Funding
- NIDDK Support