Loops of Henle
The Loops of Henle in the juxtamedullary nephrons (remember, they are close to the medulla and have long loops of Henle) create a vertical osmotic gradient. This vertical osmotic gradient is essentially an increase in osmolarity as you go deeper into the kidney. It can be used to create urine of varying concentrations- otherwise you'd be stuck with only being able to create urine of 300mOsm/L (the standard osmolarity of the extracellular fluid). The vertical osmotic gradient can produce urine as dilute as 100mOsm/L or as concentrated as 1200mOsm/L.
The most important thing with regards to the production of the vertical osmotic gradient is that the descending and ascending limbs of the Loop of Henle are permeable to different things. The descending limb is permeable to water but not salt, and the ascending limb is permeable to salt and not water.
Salt is actively transported out of the ascending loop of Henle. This increases the osmolarity of the surrounding interstitial fluid. This increase of osmolarity also causes passive diffusion of water out of the descending loop of Henle, which also increases the osmolarity of the fluid in the descending loop. Since less salt is pumped out as you go up the ascending loop of Henle (due to most of the salt already having been pumped out by the pumps near the bottom), what you get is a higher salt concentration and higher osmolarity in the tubules and interstitial fluid near the bottom of the loop, and a lower salt concentration and lower osmolarity near the top of the loop.
Hopefully that made sense- I'm not 100% sure if I've grasped this all too well, let alone explained it well.
The Loop of Henle is also home to a special co-transporter: the Na+/Cl-/K+ cotransporter in the luminal membrane (presumably of the ascending loop, as the descending loop is impermeable to salt). Two Cl- ions are transported out for every Na+ and K+ ion. Just like in the proximal tubule, this is secondary active transport as while it doesn't require energy on its own, it requires a concentration gradient that is produced by the energy-consuming Na+/K+ pump.
Another interesting point to mention is that different animals with different urine-concentrating needs have differences in their Loops of Henle. Beavers, who are surrounded by water, don't have as much of a need to conserve as much water as possible. They only have very short loops of Henle which can produce concentrations of up to 500mOsm/L. On the other hand, desert hopping mice have very long loops of Henle which can produce concentrations of up to 9400mOsm/L.
Now, in case you ever wanted to know why you can't drink seawater, here's an explanation! As mentioned earlier, we can produce urine of a concentration of up to 1200mOsm/L. Sea water has a concentration of 2400mOsm/L. Hence, if we drank one litre of seawater, we'd need to pee out two litres just to get rid of all of the salt. That means that we'd become even more dehydrated than we were before we drank the seawater! (Those desert mice would have no issue though. Lucky them.)
Urea
Urea, produced from the breakdown of proteins, also contributes to the ability of the nephrons to concentrate urine. Reabsorption of water in the proximal tubule causes concentration of urea to be higher inside the tubules than outside. This causes urea to diffuse down its concentration gradient and become reabsorbed. The proximal tubules are only somewhat permeable to urea, however, so normally only around 50% of urea is reabsorbed.
As you go down the tubule, however, the concentration of urea in the interstitial fluid is higher than that in the descending Loop of Henle. This allows urea to be secreted into the Loop of Henle.
The ascending Loop of Henle and distal tubule are impermeable to urea. Whatever urea they have, they keep. Water is still being moved out, however, resulting in increasing concentrations of urea.
Finally, the collecting ducts receive urine with a high concentration of urea from the distal tubule. As the collecting duct is reasonably permeable to urea, urea can diffuse out into the interstitial fluid. As the permeability increases as you go down, more urea can diffuse out as you go down, contributing to the vertical osmolarity gradient.
All in all, the reabsorption of urea in the proximal tubule and collecting duct allows urea to contribute to the osmolarity of the surrounding fluid, as well as to the vertical osmolarity gradient.
As urea is a product from the breakdown of protein, people on high-protein diets are better able to concentrate urine, and malnourished people are less able to concentrate urine.
The Distal Tubule and Collecting Duct
I've already written about the reabsorption of water and salts in the proximal tubule and Loop of Henle, but I haven't written about the collecting duct yet. The collecting duct is more interesting because its ability to reabsorb water and salts depends on the action of hormones such as vasopressin (a.k.a. ADH- antidiuretic hormone) and aldosterone.
Water Reabsorption
First, we'll have a look at water. Osmoreceptors in the hypothalamus are sensitive to changes in osmolarity. When osmolarity increases, this is a sign that the body needs to conserve more water to return osmolarity back to normal. Hence an increased osmolarity causes osmoreceptors to send messages to the posterior pituitary, which releases vasopressin. Vasopressin binds to V2 receptors on the basolateral membrane of distal tubule or collecting duct cells. V2 receptors are G-protein coupled receptors that insert AQP-2 (aquaporin 2) water channels on the luminal membrane. Water can thus diffuse through AQP-2 into the cell, and then through AQP-3 or AQP-4 channels (which are permanently positioned on the basolateral border) in order to be reabsorbed into the body. Water diffuses down the vertical osmotic gradient created by the Loop of Henle.
When osmolarity is decreased, no vasopressin is secreted and thus no AQP-2 is inserted into the luminal membrane. Any AQP-2s on the membrane are sequestered if the cells don't get any stimulation by vasopressin. This causes the luminal membrane to become impermeable to water. As the osmolarity of the fluid at the top of the ascending loop of Henle is 100mOsm/L, the minimum urine concentration of 100mOsm/L is produced.
Vasopressin is also released in response to decreased blood pressure. However, blood pressure must decrease significantly (larger than 10% decrease) for this to kick in.
Other factors that affect vasopressin/ADH release include:
- Nicotine- increases ADH
- Emotional stress- increases ADH
- Swallowing- decreases ADH. Swallowing is picked up by oropharyngeal mechanoreceptors, and it's why you still need to pee when you drink isotonic saline.
- Alcohol- decreases ADH. This is why people need to pee more when they drink.
Salt Reabsorption
Salt is also important for regulation of blood pressure, as wherever salt goes, water will follow. In fact, blood pressure is a large factor governing the regulation of salt reabsorption.
Granular cells (mentioned in my post about filtration) secrete renin in response to low blood pressure (which they can detect directly, as they act as baroreceptors). They can also sense a decrease in renal sodium directly, and are also stimulated by the sympathetic nervous system (which kicks in when blood pressure is low).
Renin converts angiotensinogen, released from the liver into the circulation, to angiotensin I. (Protip: a name that ends with -gen is generally an enzyme precursor. For example, pepsinogen becomes pepsin, as I'll talk about when I talk about gastrointestinal physiology.) As angiotensin I passes through the lungs, it is converted by angiotensin-converting enzyme into angiotensin II. Angiotensin II stimulates release of aldosterone from the adrenal cortex. Aldosterone increases the number of Na+ channels in the luminal membrane of the collecting duct and Na+/K+ pumps in the basolateral membrane, which in turn causes reabsorption of salt. This pathway is collectively known as the RAAS (Renin-Angiotensin-Aldosterone System) pathway.
Aside from increasing aldosterone, angiotensin II also has more direct effects. It can directly cause vasoconstriction of the afferent and efferent arterioles, reducing GFR and thus reducing salt and water loss. Angiotensin II can also stimulate the brain to produce more vasopressin/ADH, again causing reduced water loss. Stimulation of the brain by angiotensin II also increases thirst, driving the person to up their water intake.
While ADH/vasopressin is mostly sensitive to changes in osmolarity, the RAAS pathway is mainly sensitive to changes in blood pressure through the mechanisms outlined above. The RAAS pathway is useful for keeping blood pressure up.
Opposing the RAAS system is the ANP (atrial natriuretic peptide), which reduces blood pressure. It is activated when blood pressure is relatively high (8-10% higher than normal). It is secreted from the atria when the atria are stretched, as when blood pressure is high. ANP has quite widespread effects- it inhibits the sympathetic nervous system, directly inhibits Na+ reabsorption, and decreases ADH, renin and aldosterone.
In Practice...
How does all of this work in real life? Well, let's take a look at three scenarios.
- A person drinks a large volume of water. This decreases osmolarity, which is picked up by osmoreceptors. This inhibits ADH, causing aquaporins in the distal tubule and collecting duct to be sequestered. Thus, more water is lost as urine.
- A person drinks a large volume of water and exercises. This has similar effects on osmolarity. However, water loss doesn't happen right away- the activation of the sympathetic nervous system causes vasoconstriction and a reduction in glomerular filtration rate. This delays the loss of water as urine.
- A person drinks isotonic saline. This is an interesting case. Osmolarity does not change, and thus there should be no change in ADH. However, you still do lose this water. This is probably due to other mechanisms, such as the activation of the oropharyngeal (swallowing) reflex, which decreases ADH.
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