KIDNEY II - PRODUCTION OF CONCENTRATED URINE BY THE KIDNEY


Define osmolality and its importance to renal function

Basically a measure of water concentration, the higher the solution osmolality, the lower the water concentration. Important because it drives the movement of water in and out of the lumen and cells. Also what is detected by the hypothalamus in maintaining constant plasma osmolarity.

Describe the processes of salt and water absorption throughout the nephron.

SALT:

Na+

CONSISTENT AND UNCHANGED IN THE NEPHRON

The Na+ is absorbed from the lumen where:

1) we utilise it to create a gradient that other molecules can ride to get into the cell (the proximal tubule)

2) we create a solute concentration gradient in the medulla (so that water can be effectively reabsorbed and that we can create urine of varying concentrations later in the collecting duct)

AFFECTED BY HORMONES

1) Increased Na+ reabsorption in the proximal convoluted tubule due to Angiotensin II attaching to angiotensin type I receptors and increasing the water reabsorption

2) Increased Na+ reabsorption, and therefore water reabsorption in the DCT and CD due to Aldosterone (from ADH)

Cl-

Just follows Na+ flow due to the electrical gradient

So: Salt is reabsorbed in:

1) the proximal convoluted tubule

2) the ascending loop of Henle

3) (maybe if aldosterone) the distal convoluted tubule

4) (maybe if aldosterone) the collecting duct

WATER

Its flow depends on two things:

1) the osmolarity (which we control with Na+)

2) the permeability of the tubule to water (which we control with the presence or absence of aquaporins

Important concept!

The permeability of the lumen/cells to water is of great significance:

1) if a cell is fully permeable to water, then the osmolarity of that cell, the blood vessels near it, and the lumen of the duct will all be the same: this is the case in the glomerular capsule and proximal convoluted tubule.

2) If the cells are not permeable to water then we can control the concentrations of fluid within them: in the ascending loop of Henle, the osmolarity becomes smaller and smaller because we are removing solute, but we are not letting water follow it.

3) In the collecting duct, the cells can be either way, this is the only step we can control the amount of water reabsorbed or excreted. If there is ADH: aquaporins will be added to the membranes: permeable to water: so the concentration of urine will match that of its surroundings, in this case, the very high osmolarity of the medulla: this will be concentrated urine. If there is no ADH, there will be no aquaporins, no water can leave the CD, there will be no equality in osmolarity, and the concentration of urine will be the same as that which entered the collecting duct, irrespective of the high osmolarity of the medulla, because the water cannot leave! This is how we can control the concentration of urine we produce!!

Where can water flow:

1) the proximal convoluted tubule: this is where we are reabsorbing most of the things we need from the filtrate, so a lot of water will follow it

2) the descending loop of Henle: this is where water is reabsorbed: there is an increasing osmolarity in the loop and therefore increasing amounts of water will leave the filtrate

3) the distal convoluted tubule: the absorption of water here depends on the presence or absence of ADH and aldosterone as described above: this is the only step where we can control the concentration of urine and the amount of water absorbed or excreted!

Describe the mechanism of production of concentrated urine

You produce about 600mosmol of waste products each day. Because the highest osmolarity of the medulla (and therefore urine) is 1400mosmol/l, the obligatory water loss is 0.428l of urine each day.

MECHANISM 1: THROUGH INCREASING WATER REABSORPTION

Some of the last steps were already described above: the presence of aldosterone causes the aquaporins to be added to the collecting duct, which passes through the increasing osmolarity of the medulla, which leads to increasing amounts of water leaving the tubule and being reabsorbed into the blood and producing concentrated urine. But what steps lead to this?

Osmoreceptors in the supraoptic and paraventricular nuclei of the brain detect the increased osmolarity of the ECF surrounding them, they then cause the release of ADH from the posterior pituitary gland.

The ADH then binds to V2 receptors (G-protein coupled) on the cells of the duct which then add AQP-2, aquaporin 2 channels to the CD. AQP4 and AQP3 channels are permanently located on the basolateral side of the lumen, and they allow the movement of this water into blood vessels.

The osmoreceptors also stimulate the lateral preoptic area to cause conscious thirst.

How is the mechanism so fast? even though it affects the presence or absence of aquaporins of the luminal membrane of the cells, ADH does not actually cause the aquaporins to be synthesised, the aquaporins are actually located in an exocytotic vessel inside the cell. The presence of ADH causes this vessel to fuse with the membrane, presenting the channels on the surface. When ADH is not present, the plasma membrane endocytoses again to form an intracellular vessel.

CHANGES IN OSMOLARITY DETECTED BY THE BRAIN

MECHANISM 2: THROUGH INCREASING Na+ REABSORPTION, WITH WATER FOLLOWING

This mechanism is quite different and a bit more complicated.

1) low BP is detected by baroreceptors in juxtaglomerular/granular cells - first by the macula densa which start a g-protein cascade and then cause the release of ATP into the ECF, which is then converted into adenine, which then causes the contraction of the afferent arteriole?

2) renin is released by the juxtaglomerular cells starting a cascade which ends in aldosterone (shown in the image on the left)

3) angiotensin itself has effects on the nephron:

- it causes vasoconstriction of the afferent arteriole

- it stimulates ADH production (angiotensin type II receptors in brain)

- It stimulates thirst (angiotensin type II receptors in brain)

4) aldosterone itself promotes Na+ resabosrtion into the cell via Na+/H+ anti porters in the distal convoluted tubule and collecting duct, therefore promoting blood flow out of these vessels

Describe the counter-current mechanism

I find the easiest way to understand the counter-current mechanism is by understanding that it is simply a positive feed-back mechanism with the goal of increasing the osmolarity of the medulla.

Why would we want this? Well, firstly, a high medulla osmolarity promotes a lot of water leaving the descending loop of Henle, and is therefore important in water retention. And secondly, a high medulla osmolarity around the collecting duct allows us to control the concentration of urine we produce. Since we can control the permeability of the CD, and if it is fully permeable then the fluid within it will be of equal osmolarity to the fluid surrounding it, we have the option to create urine as concentrated as 1400mOsm or as dilute as 100mOsm.

So, how does it actually work?

Well, first lets understand the structure of the loop of Henle: the descending duct is permeable to water, and the ascending duct is impermeable to water, but contains a special type of transporter, the NKCC transporter.

Just like (almost) all the other parts of the nephron, the ascending duct contains a Na+/K+ pump on its basolateral side. On the luminal side, there is a pump for Na+, K+ and two Cl- ions simultaneously: secondary active transport (note the equality in charge). This removes the ions from the filtrate as it passes up the ascending loop. Note that the loop itself is impermeable to water, so we are pumping out ions, but water cannot follow them.

- Since at this point, the filtrate is moving from down up, there will be less and less ions to remove from the filtrate as it passes through the ascending loop, so the osmolarity of the fluid in the medulla will therefore increase (since water cannot follow outside) and the osmolarity of the filtrate will increase (since ions are being pumped out but water remains inside).

Remember I said there was positive feedback? Well, the more water is removed from the descending limb (and more and more water is removed as it passes into the higher concentrations of the medulla formed by the ascending limb), the higher the osmolarity of the fluid entering the ascending limb, and therefore, the more ions can be removed from the ascending limb, and the higher the concentrations of the medulla, which will therefore promote more water leaving from the next filtrate entering - and on and on. This is how the high osmolarity of the medulla is maintained by itself!

Describe the cycling of urea

Well, this drawing really describes it all.

1) the Bowmann's capsule is fully permeable to urea so it enters the nephron

2) the proximal convoluted tubule is partially permeable to urea, so it flows out with the increasing osmolarity as water and salts are absorbed, about 50% is reabsorbed

3) the descending loop of Henle is permeable to urea, and there is a high concentration of urea in the medulla (read below) so some of it flows back into the lumen

4) the ascending loop of Henle and distal convoluted tubule are impermeable to urea, so whatever concentration is left at this point will remain there

5) the CD is permeable to urea in increasing amounts, so more and more of it leaves the duct - this is important in maintaining the osmolarity gradient in the medulla

Implications:

You need urea to concentrate urine effectively (to maintain high medullary osmolarities) urea is a byproduct of protein breakdown, therefore protein is essential.

Why is urea so concentrated in urine if so much of it is reabsorbed?

Although a lot of it is reabsorbed, remember that so much more water is reabsorbed, so relatively, its concentration in the urine ends up being very high.

Explain the role of ADH in the collecting duct

Done already :)

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