Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC)

The aldosterone-sensitive distal nephron (ASDN) includes the late distal convoluted tubule 2, the connecting tubule (CNT) and the collecting duct. The appropriate regulation of sodium (Na⁺) absorption in the ASDN is essential to precisely match urinary Na⁺ excretion to dietary Na⁺ intake whilst taking extra-renal Na⁺ losses into account. There is increasing evidence that Na⁺ transport in the CNT is of particular importance for the maintenance of body Na⁺ balance and for the long-term control of extra-cellular fluid volume and arterial blood pressure. Na⁺ transport in the CNT critically depends on the activity and abundance of the amiloride-sensitive epithelial sodium channel (ENaC) in the luminal membrane of the CNT cells. As a rate-limiting step for transepithelial Na⁺ transport, ENaC is the main target of hormones (e.g. aldosterone, angiotensin II, vasopressin and insulin/insulin-like growth factor 1) to adjust transepithelial Na⁺ transport in this tubular segment. In this review, we highlight the structural and functional properties of the CNT that contribute to the high Na⁺ transport capacity of this segment. Moreover, we discuss some aspects of the complex pathways and molecular mechanisms involved in ENaC regulation by hormones, kinases, proteases and associated proteins that control its function. Whilst cultured cells and heterologous expression systems have greatly advanced our knowledge about some of these regulatory mechanisms, future studies will have to determine the relative importance of the various pathways in the native tubule and in particular in the CNT.