[box type=”download”] Water permeability of this region and the effect of ADH upon water + urea handling Role of urea in maintenance of medullary osmolality Relation of potassium excretion to tubular flow and the implication for diuretic therapy Roles of PTH and activated Vitamin D in the handling of calcium in this region [/box]
The distal tubule and collecting duct
Fluid entering the distal tubule is hypotonic (∼90 mosmol/kg H2O).
More Na+ is reabsorbed in principal cells via the Na+ channel ENaC, which is inhibited by atrial natriuretic peptide (ANP); expression of ENaC and thus Na+ reabsorption is increased by aldosterone.
This is compensated by the opposite movement of K+ through ROMK.
The distal tubule and cortical collecting duct are impermeable to urea.
They are also impermeable to water, except in the presence of antidiuretic hormone (ADH, vasopressin), which causes water channels (aquaporins) to insert into the apical membrane.
In the presence of ADH, water diffuses into the cortical interstitium, and the tubular fluid becomes concentrated, reaching a maximum osmolality of ∼290 mosmol/kg H2O (i.e. isotonic with plasma).
However, the fluid differs from plasma as large quantities of Na+, K+, Cl− and HCO3− have been reabsorbed, their place having being taken by urea.
This is concentrated as water is reabsorbed, because the distal tubule and cortical collecting duct are impermeable to urea.
The medullary collecting duct also becomes permeable to water in the presence of ADH.
Water is reabsorbed due to the high osmolality of the medullary interstitium.
The final urine osmolality can therefore reach 1400 mosmol/kg H2O under conditions of maximum ADH stimulation; in the absence of ADH, urine is dilute (∼60 mosmol/kg H2O).
Although only 15% of nephrons have loops of Henle that pass deep into the medulla, and so contribute to the high medullary osmolality, the collecting ducts of all nephrons pass through the medulla and therefore
The medullary collecting duct is relatively permeable to urea, which diffuses down its concentration gradient into the medulla and then into the ascending loop of Henle.
Urea is therefore ‘trapped’ providing ∼50% of the osmolality in the medulla.
ADH increases the permeability of the medullary collecting duct to urea and hence its reabsorption by activating epithelial uniporters (facilitated diffusion); this further increases the medullary osmolality and allows the production of more concentrated urine.
Potassium has largely been reabsorbed by the time the distal tubule is reached, and so excretion is regulated by secretion in the late distal tubule.
K+ is actively transported into principal cells by basolateral Na+ pumps, and passively secreted via ROMK channels and K+–Cl− cotransport; the former is promoted by the negative luminal charge caused by reabsorption of Na+ through ENaC.
Secretion is therefore driven by the concentration gradient between the cytosol and tubular fluid.
However, secreted K+ will reduce the gradient unless it is washed away, and so K+ excretion is increased as tubular flow increases.
Diuretics therefore often lead to K+ loss.
K+ secretion is increased by aldosterone, which enhances Na+ pump activity and apical membrane K+ permeability.
Perturbations of K+ homeostasis are often associated with acid–base disorders.
Calcium reabsorption in the distal tubule is regulated by parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (active form of vitamin D).
PTH activates Ca2+ entry channels in the epithelial apical membrane, and a basolateral Ca2+ ATPase that is also activated by 1,25- dihydroxycholecalciferol.
Ca2+ removal is assisted by an Na+–Ca2+ antiporter.
Ca2+-binding proteins prevent cytosolic free Ca2+ from rising detrimentally.
PTH also inhibits phosphate reabsorption.