The Effect of EGF Inhibition on Salt‐Sensitivity
Authors: King-Medina Keyona N. , Mistry Abinash , Mallick Rickta , Hoover Robert S. 
Published: April 2020

Every year in the United States, more than 3 million adults are determined to have high blood pressure. The prevalence of hypertension continues to rise and the federal medical spending for the hypertensive population is approximately 131 million dollars more than that for the non‐hypertensive population. This has led to a heightened interest in the study of blood pressure (BP) regulation because the underlying mechanism for hypertension remains unclear. Studies have shown that the epidermal growth factor (EGF) decreases the open probability of the epithelial‐Na+ channel (ENaC) located 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) located along the apical surface of the kidney distal convoluted tubule (DCT). Our laboratory has investigated the whether EGF regulates NCC. We performed various in vitro experiments such as cell surface biotinylation, standard immunoblotting and immunoprecipitation using mouse distal convoluted (mDCT‐15) cells. Ultimately, we found that increasing EGF led to a decrease in NCC surface expression with increase endocytosis of surface NCC. Overall, the findings from our studies and the results from other researchers, collectively suggested that EGF decreases the activity of two key mediators of salt‐sensitive blood pressure, ENaC and NCC. Therefore, this served as the rationale for investigating whether EGF inhibition affects the salt‐sensitivity of blood pressure. We hypothesized that the inhibition of EGF would increase the blood pressure (BP) in response to a higher dietary Na+ intake. Using radio‐telemetry, we collected the systolic blood pressure (SBP) measurements in five male mice ages 6–7 weeks old. These animals received a low Na+ diet (0.4% Na chow) for 6 days and high Na+ diet (4% Na chow) for 8 days. Over this 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. The results for the change in nocturnal SBP (when the mice are awake) while receiving low Na+ diet (0.4% Na+ chow) versus high Na+ diet (4% Na+ chow), showed the experimental group had a greater increase in SBP in response to a higher dietary Na+ intake (E group: −7.70 ± 0.17 vs. C group: −0.311 ± 0.29 mmHg, p<0.001). The delta (Δ) for the difference in BP change when increasing the dietary Na+ intake was greater for the experimental group of mice (Δ = −7.40 mmHg, p<0.001). Therefore, our data strongly suggests that inhibition of EGF increases salt sensitivity in blood pressure (BP). In continuation of our investigation, we will explore the role that NCC and ENaC play in this effect. Our novel findings suggest there could be another molecular pathway of interest for effective treatment in the hypertensive population, especially in persons with salt‐sensitive hypertension.

Support or Funding Information

NIH T32:5T32DK007656‐28 (King‐Medina)VA Merit Awards: I01BX000994 (Hoover)