Regulation of distal tubule sodium transport: mechanisms and roles in homeostasis and pathophysiology

Regulated Na(+) transport in the distal nephron is of fundamental importance to fluid and electrolyte homeostasis. Further upstream, Na(+) is the principal driver of secondary active transport of numerous organic and inorganic solutes. In the distal nephron, Na(+) continues to play a central role in controlling the body levels and concentrations of a more select group of ions, including K(+), Ca(++), Mg(++), Cl(−), and HCO(3)(−), as well as water. Also, of paramount importance are transport mechanisms aimed at controlling the total level of Na(+) itself in the body, as well as its concentrations in intracellular and extracellular compartments. Over the last several decades, the transporters involved in moving Na(+) in the distal nephron, and directly or indirectly coupling its movement to that of other ions have been identified, and their interrelationships brought into focus. Just as importantly, the signaling systems and their components—kinases, ubiquitin ligases, phosphatases, transcription factors, and others—have also been identified and many of their actions elucidated. This review will touch on selected aspects of ion transport regulation, and its impact on fluid and electrolyte homeostasis. A particular focus will be on emerging evidence for site-specific regulation of the epithelial sodium channel (ENaC) and its role in both Na(+) and K(+) homeostasis. In this context, the critical regulatory roles of aldosterone, the mineralocorticoid receptor (MR), and the kinases SGK1 and mTORC2 will be highlighted. This includes a discussion of the newly established concept that local K(+) concentrations are involved in the reciprocal regulation of Na(+)-Cl(−) cotransporter (NCC) and ENaC activity to adjust renal K(+) secretion to dietary intake.