The Loop Of Henle And Distal Nephron
The loop of Henle and distal nephron allow urine to be concentrated
through the creation of a high
osmolality in the medulla, which drives the reabsorption of water from the collecting
ducts. The distal nephron also regulates K+ and Ca2+ excretion and
acid base status (Chapter 36).
The loop of Henle
Fluid entering the descending limb
of the loop of Henle is isotonic with plasma (∼290 mosmol/kg H2O). The
generation of high osmolality in the medulla depends on the differential
permeabilities to water and solutes
in different regions, the active transport of ions in the thick ascending limb and the counter-current
multiplier. The thin descending limb is permeable to water but
impermeable to urea, whereas the ascending limb is impermeable to water
but permeable to urea (Fig. 34a); it is also very highly permeable to Na+ and
Cl−. The thick ascending limb actively reabsorbs Na+ and Cl− from the
tubular fluid by means of apical Na+–K+–2Cl− cotransporters;
Na+ is primarily transported across the basolateral membrane by Na+ pumps (some
by Na+–HCO − cotransport), and Cl− by diffusion (Fig. 34b and b ). K+ leaks
back into the lumen via apical ROMK K+ channels, creating a positive
charge that drives the reabsorption of cations (Na+, K+, Ca2+,
Mg2+) through paracellular pathways. As the thick ascending limb is
impermeable to water, the reabsorption of ions reduces the tubular fluid
osmolality (to ∼90 mosmol/kg H2O) and increases the interstitial fluid osmolality,
creating an osmotic difference of ∼200 mosmol/kg H2O.
Counter-current multiplier (Fig. 34c). The increased interstitial
osmolality causes water to diffuse out of the descending limb, and some Na+ and
Cl− to diffuse in, concentrating the tubular fluid (Fig. 34c). As this
concentrated fluid descends, it travels in the opposite direction to fluid
returning from the still higher osmolality regions of the deep medulla. This counter-current
arrangement creates an osmotic gradient, causing Na+ and Cl− to diffuse out
of the ascending limb (diluting the ascending fluid), and water to diffuse out
of the descending limb (further concentrating the descending fluid). This
effect is potentiated by the fact that the ascending limb is impermeable to
water, but highly permeable to Na+ and Cl−, and also by the recycling of urea
between the collecting ducts and ascending limb, which makes an important
contribution to urine concentration (see below). At the tip of the loop of
Henle, the interstitial fluid can reach an osmolality of ∼1400 mosmol/kg H2O, due in equal parts to NaCl and urea.
The blood supply to the medulla is
prevented from dissipating the osmotic gradient between the cortex and medulla
by the counter-current exchanger arrangement of the vasa recta capillaries
(Fig. 34d). The vasa recta also removes water reabsorbed from the loop of Henle
and medullary collecting ducts. It should be noted that O2 and CO2 are also
conserved, so that, in the deep medulla, Po2 is low and Pco2 is high.
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 (Chapter
35). The movement of Na+ through ENaC is charge compensated by the opposite movement of K+ through ROMK (Fig.
34f and f ). The distal tubule and cortical collecting duct are
impermeable to urea. They are also impermeable to water, except in the presence
of anti- diuretic hormone (ADH, vasopressin) (Chapter 35),
which causes water channels (aquaporins) to insert into the apical
membrane (Fig. 34e and e ). 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 (Fig. 34a). 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) (Chapter 35). Although only 15% of nephrons
have loops of Henle that pass deep into the medulla, and so contribute to the
high medullary osmolality (Chapter 31), the collecting ducts of all nephrons
pass through the medulla and therefore concentrate urine.
Urea. 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 (Fig. 34a). Urea is
therefore ‘trapped’ and partially recycled, so maintaining a high concentration
and providing ∼50% of
the osmolality in the medulla (see above). 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. 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 (Fig. 34f and f ). 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 (Chapter 36). K+ secretion is increased by aldosterone,
which enhances Na+ pump activity and apical membrane K+ permeability (Chapter
35). Perturbations of K+ homeostasis are often associated with acid–base
disorders (Chapter 36).
Calcium. 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 (Fig. 34g and g ). PTH also inhibits phosphate
reabsorption (Chapter 33). Ca2+ regulation is discussed in Chapter 48.
