Salt‐dependent inhibition of the epithelial sodium channel (ENaC) by Bradykinin

Abstract

Kalikrein‐kinin system in the kidney promotes natriuresis to decrease blood pressure. Deletion of Bradykinin (BK) receptors results in salt‐sensitive hypertension indicating possible augmentation of Na+ transport and ENaC activity in the distal nephron. In this study, we tested a role of BK in adaptation of ENaC to changes in systemic salt status. Using patch clamping in split‐opened distal nephrons, we found that BK reversibly inhibits ENaC. BK had no effect on ENaC in mice lacking Bradykinin receptors (B1,B2−/−). Under normal Na+ intake (0.32%), ENaC Po was modestly elevated in B1,B2−/− compared to WT mice. High Na+ intake (2%) greatly augmented this difference. DOCA treatment similarly increased ENaC activity in both strains suggesting aldosterone‐independent nature of BK regulation of ENaC. Angiotensin converting enzyme (ACE) represents the major pathway of BK degradation. Systemic inhibition of ACE with captopril decreases ENaC activity in WT but not in B1,B2−/− mice. We further determined that captopril greatly potentiated BK signaling in the distal nephron resulting in a stronger ENaC inhibition. We concluded that BK cascade has its own specific role in blunting ENaC activity particularly under conditions of elevated Na+ intake. Augmentation of BK signaling in the distal nephron inhibits ENaC‐mediated Na+‐reabsorption contributing to the natriuretic and antihypertensive effects of ACE inhibition.