EGF deficiency contributes to the development of salt‐sensitive hypertension via upregulation of ENaC activity

Abstract

Amiloride‐sensitive sodium entry, via the epithelial Na+ channel (ENaC), is the rate‐limiting step for Na+ absorption in the aldosterone sensitive distal nephron (ASDN). Dysfunction and aberrant regulation of ENaC leads to a spectrum of diseases associated with abnormal Na+ handling, including hypertension. The contribution of ENaC appears to be of critical importance in Dahl SS hypertensive rats. Members of the epidermal growth factor (EGF) family play an important role in regulation of transepithelial Na+ transport in the kidney. A combination of electrophysiological, histochemical, molecular and chronic studies in vivo and in vitro was used to investigate how ENaC is regulated by EGF and how changes in this pathway contribute to salt‐induced hypertension in SS rats. 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. In contrast, ENaC activity was upregulated in SS rats fed a high salt diet. To directly evaluate EGF effect on the development of hypertension and ENaC activity, EGF was intravenously infused and MAP was monitored continuously. Chronic infusion of EGF (2 mg/h; i/v) in SS rats fed a high salt prevented the development of hypertension, increased Na+ excretion and decreased ENaC activity in the ASDN. Furthermore, histological analysis revealed that EGF attenuated renal glomerular and tubular damage.