EGF/RhoGDIα/Rac1 pathway modulates ENaC activity and contributes to the development of salt‐sensitive hypertension (892.27)

Abstract

Epithelial sodium channel (ENaC) performs sodium reabsorption in the aldosterone sensitive distal nephron. Amongst other hormonal agents, ENaC‐mediated sodium reabsorption is regulated by the members of epidermal growth factor (EGF) family; specifically, chronic treatment with the EGF‐family members downregulates ENaC activity in vitro. We have recently shown that EGF deficiency is involved in improper ENaC activity and contributes to the development of salt‐induced hypertension in Dahl salt‐sensitive (SS) rats. Investigation of signaling pathways potentially involved in regulation of ENaC by EGF, revealed that high salt diet in SS rats decreases abundance of Rho GDP‐dissociation inhibitor 1(RhoGDIα), a well characterized modulator of Rho‐family small GTPases. RhoGDIα deficiency in cultured mCCDcl1 principal cell line increases ENaC‐mediated current formation and causes enhanced response of ENaC activity to EGF treatment. Further experiments revealed that these effects are mediated via Rac1 small GTPase. We conclude that renal EGF deficiency in the SS rats on a high salt diet provokes excessive ENaC activity via RhoGDIα/Rac1pathway and contributes to the development of salt‐induced hypertension.Grant Funding Source: Supported by AHA, NHLBI