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 HCO 3 − reabsorption. Two subtypes of intercalated cells are located along the collecting ducts: – Type A are involved in acid and HCO 3 − secretion – Type B are involved in bicarbonate secretion and chloride reabsorption.

Type A intercalated cells express apical H + -ATPase and basolateral Cl − /HCO 3 − exchanger. The H + generated by carbonic anhydrase is pumped into the lumen and binds with NH 3. HCO 3 − is conserved by exchange with Cl − on the basolateral side. Cl − exchanged with HCO 3 − is recycled back to the interstitium via basolateral Cl − channels. Type B intercalated cells have these channels opposite to Type A cells to excrete HCO 3 − 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 (NH 3 ). NH 3 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, a 2 -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 HCO 3 − 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 HCO 3 − 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 potential 2.stimulation of H + -ATPase activity. Finally, endothelin 1 stimulates HCO 3 − reabsorption and H + secretion along the collecting duct.