Ion transport along the nephron is essential for the reabsorption of sodium and water, maintenance of plasma volume, blood pressure and production of urine. The Loop of Henle contributes to the absorption of approximately 25% of filtered sodium and can be targeted by diuretic therapy.
The Loop of Henle has a hairpin configuration with a thin descending limb and both, a thin and thick ascending limb (TAL). The thin descending and ascending segments have thin, squamous epithelial membranes with minimal metabolic activity. The TAL has cuboidal epithelial membranes and is quite metabolically active.
In this article we will describe the ion transport and water movement that occurs within the Loop of Henle, and we will consider the clinical relevance of this.
Thin Descending Limb
The descending limb is highly permeable to water, with reabsorption occurring passively via aquaporin-1 (AQP1) channels. Small amounts of urea, sodium (Na+) and other ions are also reabsorbed. As mentioned above, water reabsorption is driven by the counter-current multiplier system set up by the active reabsorption of sodium in the TAL.
Thin Ascending Limb
The thin ascending limb is impermeable to water, due to it having no aquaporin channels. Na+ reabsorption occurs passively through epithelial Na+ (eNaC) channels and Chloride (Cl–) ions are reabsorbed in the thin ascending limb through Cl– channels. There is some paracellular movement of Na+ and Cl– because of the difference in osmolarity between the tubule and the interstitium.
Thick Ascending Limb (TAL)
The primary site of sodium reabsorption in the Loop of Henle is the thick ascending limb (TAL). The TAL is impermeable to water. Sodium reabsorption is active – the driver is the Na+/K+ ATPase on the basolateral membrane which actively pumps 3 Na+ ions out of the cell and 2 potassium (K+) ions into the cell. So by creating a low intracellular concentration of sodium, the inside of the cell becomes negatively charged, creating an electrochemical gradient.
Sodium then moves into the cell (from the tubular lumen) down the electrical and chemical gradient, through the NKCC2 transporter on the apical membrane This transporter moves one Na+ ion, one K+ ion and two Cl– ions across the apical membrane.
Potassium ions are transported back into the tubule by renal outer medullary potassium (ROMK) channels on the apical membrane to prevent toxic build up within the cell. Chloride ions are transported into the tissue fluid via CIC-KB channels.
The overall effects of this process are:
- Removal of Na+ whilst retaining water in the tubules – this leads to a hypotonic solution arriving at the DCT.
- Pumping Na+ into the interstitial space – this contributes to a hyperosmotic environment in the kidney medulla
There is also some paracellular reabsorption of magnesium, calcium, sodium and potassium.
As the thick ascending limb is impermeable to water, the interstitium becomes concentrated with ions, increasing its osmolarity. This drives water reabsorption from the descending limb as water moves from areas of low osmolarity to areas of high osmolarity. This system is known as counter-current multiplication and it allows the kidneys to reabsorb around 99% of filtered water
Clinical Relevance – Bartter Syndrome
Bartter syndrome is a group of autosomal recessive conditions characterised by genetic mutations in the genes coding for the NKCC2 transporter, apical potassium channel or basolateral chloride ion channel. The consequences are biochemically similar to administration of loop diuretics (see below).
Clinical features of Bartter Syndrome include:
- metabolic alkalosis
Clinical Relevance – Loop Diuretics
Loop diuretics get their name from the fact that they act on the Loop of Henle. They work by inhibiting NKCC2 transporters in the thick ascending limb, stopping sodium, potassium and chloride reabsorption. Less sodium reabsorption reduces the concentration of the renal medulla, decreasing water reabsorption in the DCT and CD. This leads to increased excretion of sodium in the urine and significant diuresis, reducing plasma volume. Thus, loop diuretics such as furosemide are usually used to treat hypervolaemia – Heart or Liver failure.
An important side-effect of loop diuretics is hypokalaemia. This is because increasing sodium delivery to the DCT, also increases potassium excretion.