The Physiology of the Distal Tubules and Collecting Ducts

General Transport Properties of Collecting Ducts

• Cortical and outer medullary collecting ducts are made up of two different cell types.

• Principal cells are responsible for water and sodium reabsorption as well as potassium secretion, and intercalated cells are involved in acid-base regulation.

• Na+ reabsorption in principal cells is linked to K+ secretion through a two-step mechanism:

1. K+ transport in and Na+ transport out of the cell from basolateral Na+/K+/ATPase which generates the driving forces for apical Na+ entry and K+ exit.

2. K+ exit occurs through apical and basolateral K+ channels. • This K+secretion and Na+ reabsorption is in a 2 K+–to-3 Na+. • Creating a lumen-negative transepithelial voltage which also favors

paracellular Cl− reabsorption.

• Apical Na+ influx is mediated by the amiloride-sensitive Na+ channel (ENaC), and provides the driving force for secondary active transport of other solutes.

• Luminal K+ secretion is driven by negative transepithelial voltage generated by Na+ reabsorption.

• Water reabsorption along the collecting duct is a facilitated process that occurs through specific water channels of the aquaporin family.

• The driving force for water reabsorption is provided mainly by the osmotic gradient generated by countercurrent concentrating mechanism in the loop of Henle.

• Na+ reabsorption along the collecting duct dilutes luminal fluid and generates an osmotic gradient favorable to water reabsorption.

• Water reabsorption along the collecting duct is controlled chiefly by vasopressin and secondarily by additional factors such as extracellular tonicity, aldosterone, insulin, and extracellular calcium.

• The collecting duct is the major site of acid secretion and HCO3

− reabsorption. • Two subtypes of intercalated cells are located

along the collecting ducts: – Type A are involved in acid and HCO3

− secretion– Type B are involved in bicarbonate secretion and

chloride reabsorption.

• Type A intercalated cells express apical H+-ATPase and basolateral Cl−/HCO3

− exchanger. • The H+ generated by carbonic anhydrase is pumped into

the lumen and binds with NH3.

• HCO3− is conserved by exchange with Cl− on the

basolateral side.• Cl− exchanged with HCO3

−is recycled back to the interstitium via basolateral Cl− channels.

• Type B intercalated cells have these channels opposite to Type A cells to excrete HCO3

− and absorb Cl−.

• Disruption of luminal negative transepithelial potential due to decreased Na+ reabsorption (aldosterone deficiency or potassium-sparing diuretic treatment) leads to type 4 (distal hyperkalemic) renal tubular acidosis.

• After its secretion, H+ is buffered by titratable acids (phosphate and creatinine) and by secreted ammonia (NH3).

• NH3 is generated in the proximal tubule through deamination of glutamine, is reabsorbed by the thick ascending limb of the loop of Henle via the luminal Na+,K+,2Cl− cotransporter, is accumulated along the corticopapillary axis via the countercurrent mechanism, and, finally, is secreted by the collecting duct.

Aldosterone

• The major role of aldosterone is to increase extracellular volume in response to volume depletion signaled by the renin-angiotensin system.

• Aldosterone plays an role in K+ homeostasis:– High extracellular K+ stimulates aldosterone secretion– K+ secretion is linked to aldosterone-regulated

Na+ reabsorption, which generates the electrical driving force for K+ secretion.

• Aldosterone controls Na+ reabsorption in principal cells through stimulation of apical ENaC and basolateral Na+,K+-ATPase .

• The early aldosterone effect can be observed after 30 minutes.

• This effect relies mostly on increased expression of active ENaC and Na+,K+-ATPase in the apical and basolateral plasma membrane.

• The long-term effect of aldosterone induces a more sustained increase in the transport capacity via synthesis of ENaC and Na+,K+-ATPase subunits.

Vasopressin

• Vasopressin binds to V2 receptor then the cAMP/PKA pathway to increase expression of ENaC and aquaporins.

• Therefore, vasopressin stimulates the reabsorption of both sodium and water.

Intracellular Sodium Concentration

• [Na+]i is the most important nonhormonal factor regulating Na+,K+-ATPase activity.

• Any increase in [Na+]i stimulates Na+,K+-ATPase, which in turn pumps more Na+ out of the cell and thereby contributes to restoration of initial [Na+]i.

• On the extracellular side, Na+,K+-ATPase is stimulated by K+.

• This effect is in part nuclear as there is activation of the PKA pathway.

Negative Modulators

• The stimulatory effect of Na+,K+-ATPase is counteracted by several negative modulators, such as prostaglandins, a2-adrenergic agonists, endothelin, dopamine, and bradykinin.

• Most of these mediators modulate intracellular concentration of cAMP at the level of its production and/or degradation, thereby indirectly controlling ENaC and Na+,K+-ATPase activity.

Water Reabsorption by Collecting Duct Principal Cells

• Increases in vasopressin cause AQP2-containing intracellular vesicles to rapidly fuse to the apical plasma membrane raising the water permeability.

• Prolonged increases in vasopressin increase AQP2 expression to increase maximal collecting duct water permeability.

• Extracellular osmolarity also regulates AQP2 abundance with increased osmolarity causing increased expression.

• Aldosterone increases AQP2 via increased translation of AQP2 messenger RNA.

• Hypercalcemia is associated with nephrogenic diabetes insipidus. – AQP2 expression and water permeability are decreased via

activation of a luminal extracellular calcium receptor.– Activation of the extracellular calcium receptor decreases AVP-

induced translocation of AQP2 from intracellular stores to the plasma membrane.

• This negative feedback increases urine volume and reduce the risk of urolithiasis in the presence of hypercalciuria.

• This also explains the volume depletion seen in malignant hypercalcemia.

Regulation of Acid-Base Transport

• Systemic acid-base status is the major mechanism controlling acid-base secretion by the collecting duct.

• Metabolic and respiratory acidosis increases whole cell H+-ATPase expression and recruitment of type A intercalated cells.

• Carbonic anhydrase expression and activity are increased, and HCO3

− secretion by type B intercalated cells is inhibited.

• A mirror image of this situation is observed during alkalosis.

• Several hormonal and local factors also contribute to regulated acid-base transport along the collecting duct.

• Angiotensin II increases HCO3− reabsorption along the

collecting duct via AT1 receptor–induced recruitment of H+-ATPase.

• Aldosterone increases H+ secretion via:1. increased Na+ reabsorption and thereby luminal-negative

transepithelial potential2. stimulation of H+-ATPase activity.

• Finally, endothelin 1 stimulates HCO3−reabsorption and

H+ secretion along the collecting duct.