EGF Deficiency in the Renal Cortex Contributes to Salt-Sensitive Hypertension via Upregulation of ENaC Activity

Abstract

Dahl salt-sensitive (SS) rats fed a high salt diet exhibit increased blood pressure and renal damage. Epithelial sodium channel (ENaC), is responsible for the fine tuning of Na+ absorption in the kidney. We and others have shown recently that members of the epidermal growth factor (EGF) family are important for maintaining transepithelial Na+ transport and that EGF biphasically modulates sodium transport in principal cells. A combination of electrophysiological, immunohistochemical, biochemical, microscopy and chronic studies in vivo and in vitro was used here to provide mechanistic insights on how ENaC is regulated by EGF and how changes in this pathway contributes to salt induced hypertension in the SS rats. Western blotting and immunohistochemistry analyses demonstrate that expression of ENaC subunits are significantly increased in SS rats fed a high salt diet and in SS versus consomic, salt-resistant SS-13BN rats. Patch clamp analysis of ENaC activity in split opened tubules also demonstrated upregulation of ENaC activity in SS rats fed a high salt diet. As measured by ELISA, EGF concentration in the kidney cortex of SS rats fed a high salt diet was significantly lower compared to rats on a low salt diet. To directly evaluate EGF effect on the development of hypertension and ENaC activity, EGF was intravenously infused and MAP was monitored continuously. Supplementation of EGF prevented the development of hypertension in SS rats and attenuated renal glomerular and tubular damage. Moreover, chronic infusion of EGF decreased ENaC activity in isolated distal nephron. Thus, EGF and related growth factors are decreased under conditions of an elevated dietary NaCl intake leading to decreased activation of the EGF receptor and thus resulting in the insertion of enhanced ENaC in the apical membrane of the principal cells.