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

Abstract

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 HCO3−, 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.

WNK1 is a chloride-stimulated scaffold that regulates mTORC2 activity and ion transport

“…Finally, in regard to the implications of our present findings for K + homeostasis, it is worth emphasizing that concomitantly inhibiting WNK1 kinase activity through K + while stimulating its interactions with SGK1 and mTORC2 provides a parsimonious mechanism for rapidly shifting Na + transport from electroneutral NaCl reabsorption (which defends extracellular fluid volume) to electrogenic reabsorption (which drives K + secretion to bring down extracellular [K + ]) ( Pearce et al, 2022 ; Sørensen et al, 2019 ) ( Fig. 8 B).…”

Potassium Activates mTORC2-dependent SGK1 Phosphorylation to Stimulate Epithelial Sodium Channel: Role in Rapid Renal Responses to Dietary Potassium

“…Since the identification of mTORC2 as the hydrophobic motif kinase for AGC kinases (principally, SGK, Akt, and conventional PKC), its roles in mediating the effects of hormones and growth factors on cell growth, metabolism, and ion transport have been intensively studied. 4,8,10,[15][16][17]42 More recently, increasing evidence has pointed toward a role for mTORC2 in direct responses of renal tubule cells to extracellular [K 1 ] in the regulation of K 1 secretion 18,20,21 ; however, the transporters and channels regulated have been controversial, and the physiologically relevant signaling mechanisms have remained uncertain. [19][20][21] To gain a clearer picture of the signaling events and targets of regulation operating in vivo, this work has focused on the sequence of responses to short and medium-term K 1 administration in WT and renal tubulespecific mTORC2-deficient (TRKO) mice.…”

“…3 Renal outer medullary potassium (ROMK) and BK K 1 channels constitute the predominant pathway for K 1 movement across the apical membrane while the Na 1 channel, epithelial sodium channel (ENaC), is essential for establishing the electrical driving force for luminal secretion. 4,5 The steroid hormone aldosterone stimulates ENaC apical membrane localization and activity through the mineralocorticoid receptor (MR), which increases gene transcription and hence protein levels of numerous targets, 6,7 most notably, the serum and glucocorticoid regulated kinase type 1 (SGK1). 4 SGK1 in turn phosphorylates and inhibits the ubiquitin ligase, Nedd4-2, itself an ENaC inhibitor.…”

Extracellular intersubunit interactions modulate epithelial Na+ channel gating

“…ENaCs are also expressed in nonepithelial cells, including endothelia, vascular smooth muscle, and dendritic cells ( 1 , 2 , 3 ). In the aldosterone-sensitive distal nephron, ENaC functions together with basolateral Na + /K + -ATPase, apical renal outer medullary potassium channel and sodium chloride cotransporter, regulates Na + homeostasis and extracellular fluid volume, K + homeostasis, and blood pressure ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ).…”