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.

Keywords: 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2); Aldosterone; Aldosterone-sensitive distal nephron (ASDN); Connecting tubule (CNT); Cortical collecting duct (CCD); Early distal convoluted tubule (DCT1); Epithelial sodium channel (ENaC); Kinase 1 and 4 (WNK1 and WNK4); Late distal convoluted tubule (DCT2); Mineralocorticoid receptor (MR); Na+-Cl− cotransporter (NCC); Renal outer medullary K+ channel (ROMK); Serum and glucocorticoid-regulated kinase 1 (SGK1); mTOR complex 2 (mTORC2); With no lysine.

Fig. 1

Segment-specific sodium transport mechanisms in the distal nephron. a Schematic representation of a single nephron highlighting different segments of the distal nephron, i.e., the distal convoluted tubule with its early (DCT1) and late (DCT2) portion, the connecting tubule (CNT), the cortical collecting duct (CCD), and the outer medullary collecting duct (OMCD). b Tubule epithelial cell models illustrating segment-specific apical sodium uptake mechanisms. Basolateral sodium extrusion in exchange for potassium (3Na⁺/2 K⁺) is accomplished by the basolateral Na⁺-K⁺-ATPase in all cell types. A defining feature of both DCT1 and DCT2 is the apical Na⁺-Cl⁻ cotransporter (NCC); DCT2, but not DCT1, also expresses the epithelial sodium channel (ENaC). ENaC is the sole apical sodium uptake mechanism in CNT and CCD principal cells. In addition to playing a decisive role in fine tuning renal sodium absorption, ENaC also generates the electrical driving force necessary for K⁺ secretion meditated primarily by the apical renal outer medullary K⁺ channel (ROMK). In the late CNT and entire CCD (CNT/CCD), aldosterone (A) is the key hormonal activator of ENaC through the mineralocorticoid receptor (MR) which is protected from glucocorticoid action by 11ß-hydroxysteroid dehydrogenase type 2 (11βHSD2). In the DCT2 and early CNT (DCT2/CNT), MR appears to have constitutive activity, possibly due to low levels of 11βHSD2, allowing glucocorticoids (G) to activate the receptor. This provides a potential explanation for the aldosterone-independent but MR-dependent ENaC activity in the latter region, which is probably important for Na⁺ homeostasis and blood pressure control, as well as aldosterone-independent K⁺ secretion

Fig. 2

Coordinated regulation of ENaC and NCC by interstitial potassium. The effects of increased interstitial K⁺ on Na⁺ transport are shown for a DCT1 cell (top) and CNT/CCD cell (bottom). Baseline membrane potential is controlled primarily by Kir4.1/5.1. Increased interstitial K⁺ concentration ([K⁺]↑) depolarizes the basolateral membrane potential (V_bl↓), thus altering the electrochemical gradient for Cl⁻ across the basolateral membrane equipped with Cl⁻ channels (in particular ClC-K2 in DCT1), and eventually causes an increase in intracellular Cl⁻ concentration ([Cl⁻]↑) in both the DCT1 and CCD. Chloride can then bind to WNK1/4, which inhibits its kinase activity and prevents NCC activation in the DCT1. In the CCD, chloride-bound WNK1/4 interacts with both mTORC2 and SGK1 to increase SGK1 phosphorylation and subsequent ENaC activation. Increased electrogenic ENaC activity depolarizes the apical membrane potential (V_ap↓), thereby stimulating ROMK-mediated K⁺ secretion. Aldosterone (A) contributes to ENaC regulation in the CCD by binding to the mineralocorticoid receptor (MR) and increasing SGK1 transcription. Purple arrows indicate effects due to an increase in interstitial K.⁺ and red arrows depict the effects of aldosterone (A)