Overview

Na⁺/K⁺ handling: Na⁺ enters across the apical membrane through the epithelial sodium channel (ENaC) and is pumped out basolaterally by Na⁺/K⁺-ATPase. Because Na⁺ is reabsorbed without an accompanying anion, the lumen becomes negative (up to −40 mV), driving K⁺ secretion through apical ROMK (and flow-activated BK) channels and Cl⁻ reabsorption paracellularly. Aldosterone binds the cytoplasmic mineralocorticoid receptor (protected from cortisol by 11β-hydroxysteroid dehydrogenase type 2) and increases ENaC (via SGK1), Na⁺/K⁺-ATPase and ROMK.

Water: ADH binds the basolateral V2 receptor → Gs → cAMP → protein kinase A → phosphorylation and exocytic insertion of aquaporin-2 into the apical membrane; water exits basolaterally through AQP3 and AQP4. Long-term ADH also increases AQP2 synthesis.

K⁺ secretion increases with aldosterone, high plasma K⁺, high distal Na⁺ delivery and high tubular flow (the reason loop and thiazide diuretics cause hypokalaemia).

Location: Connecting tubule and cortical, outer and inner medullary collecting ducts.

Anatomy

Histology: Pale cuboidal cells with few organelles and a single primary cilium (flow sensor; defective cilia signalling underlies polycystic kidney disease).

Function

Na⁺ reabsorption (ENaC)
K⁺ secretion (ROMK, BK)
Water reabsorption (AQP2)

Regulation: Aldosterone (MR), ADH (V2), ANP (inhibits), plasma K⁺.

Clinical significance

Apparent mineralocorticoid excess

Deficiency or inhibition of 11β-HSD2 (genetic, or liquorice/glycyrrhizin) lets cortisol occupy the mineralocorticoid receptor → hypertension, hypokalaemia, low renin and aldosterone.

Lithium toxicity

Lithium enters principal cells through ENaC and disrupts V2/AQP2 signalling, causing nephrogenic DI; amiloride blocks its entry.

Test yourself

Antidiuretic hormone increases water reabsorption in the collecting duct mainly by:

Inserting aquaporin-2 into the apical membrane of principal cells via V2 receptors and cAMP
Inserting aquaporin-1 into the thin descending limb
Opening ENaC channels in intercalated cells
Constricting the efferent arteriole via V1 receptors

Answer: Inserting aquaporin-2 into the apical membrane of principal cells via V2 receptors and cAMP

ADH binds V2 receptors on the basolateral membrane of principal cells → Gs → cAMP → PKA → fusion of AQP2-containing vesicles with the apical membrane. Water exits basolaterally via AQP3/AQP4. AQP1 in the PCT and descending limb is constitutive.