Transcript The Physiology of the Distal Tubules and Collecting Ducts

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.
2.
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.
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 amiloridesensitive 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
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•
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
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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 potential
2. stimulation of H+-ATPase activity.
• Finally, endothelin 1 stimulates HCO3−reabsorption and
H+ secretion along the collecting duct.