Osmoregulation Flashcards
What is osmoregulation?
The regulation of osmolality.
The collecting duct modifies osmolality in the interstitial space, to drive water movement from the Loop of Henle.
Main regulation is by the ADH hormone.
What is ADH?
Anti-diuretic hormone (vasopressin).
ADH opposes the production of urine (diuresis).
Synthesised by the hypothalamus.
What is the hypothalamus?
Hypothalamic Osmo-sensors.
Cells in the hypothalamus above the pituitary gland can sense changes in osmolality.
What does the hypothalamus do when osmolality increases?
Osmolality increase, hypothalamus stimulates secretion of ADH.
Neurone cell body is in the hypothalamus, axon extends into pituitary gland.
ADH is released from the nerve terminals in the pituitary gland, and enters circulation.
What is the effect of ADH?
ADH can act on the blood vessels and cause them to vasoconstrict.
On the kidneys, ADH increases the insertion of Aquaporin 2 (AQP2) in the distal tubule and collecting duct.
How does water movement occur in the collecting duct?
Water movement is mainly transcellularly through aquaporins.
There is some paracellular movement but it is limited.
AQP3 is constitutively (always present) expressed on the basolateral membrane.
AQP2 can be inserted into the membrane by ADH presence.
What are the ADH receptors?
V2 receptors, GPCRs, on the basolateral membrane of the collecting duct.
This means they are available for hormones coming from circulation, as the medullary interstitial space is where capillaries exchange substances.
How do the V2 receptors work?
Gs coupled, which causes an increase in cAMP, and stimulates PKA.
PKA phosphorylates proteins that drive insertion of vesicles, which have proteins embedded in its walls as channels.
When vesicles are stimulated, they are inserted into the apical membrane, and allows more water movement.
This is short, rapid osmoregulation.
What is long term osmoregulation?
New proteins are made for the process of insertion of receptors, so it is sustainable, so there are changes in transcription and translation of AQP2.
This is a slow process.
What happens when there is no ADH?
The osmolality in the proximal tubule is the same as in the plasma.
As the filtrate descends down the loop of Henle, there is higher osmolality outside, so some water leaves - higher osmolality.
As filtrate ascends, some salts are pumped out, so osmolality drops low.
In the collecting duct, if there is no ADH, then there is no water reabsorption, the filtrate stays dilute, and produces a low osmolality.
What happens quantitively when there is no ADH?
Normal flow rate in the nephron is 1mil/min.
When there is no ADH, flow rate increases to 17mil/min, about a litre an hour of urine.
What is the water reabsorption levels in the kidney?
Along PCT about 70% of water is absorbed, so at the end of PCT not much water.
In loop of Henle, most water is reabsorbed in descending limb, so even less water in DCT.
In collecting duct, when there is no ADH, there is very little water reabsorption - high urine output.
What happens to water reabsorption when there is maximum ADH?
There is lots of insertion of AQP2.
So lots of water is reabsorbed in the DCT and collecting duct.
This means the urine has a very high osmolality - very concentrated, and low volume.
What is urea?
Has a role in maintaining osmolality in the renal medulla.
Movement of urea is also regulated by ADH, by expression of the urea transporter UT-A1 in the collecting duct.
What does ADH do for urea?
When there is high ADH, the UT-A1 transporter is inserted into the collecting duct.
This helps reabsorb urea, keeps the osmolality of the interstitial space high, so aids water reabsorption high.
What is urea depletion?
In the presence of selective protein starvation, urea production is low, so the kidney has a lower capacity to concentrate urine.
So ADH can help to reabsorb urea and therefore reabsorb water.
How do the cells in the medulla stop the epithelial cells shrinking under high osmolality?
The medulla accumulate a range of other organic osmolytes in the cytoplasm that are not metabolically active e.g. sorbitol, inositol, glycerphosphorylcholine and betaine.
This increases the osmolality of the cells in the loop, to match the outside of the cell, so no water movement across the membrane.
What is diabetes insipidus?
Results from a loss of ADH secretion - central diabetes insipidus, or less in sensitivity in kidney to ADH.
Loss of sensitivity is often because of a problem with the V2 receptors - nephrogenic diabetes insipidus.
What is the consequence of diabetes insipidus?
They are unable to produce concentrated urine, cannot retain water
This leads to polyuria - large urine excretion with low osmolality.
Causes dehydration and hypovolaemia, if water is not drunk excessively.
The loss of water means Na+ is left, and can become hypernatremic.
What is central diabetes insipidus?
A lack of ADH secretion caused by damage to the brain, by head injury, tumour or infection.
The treatment is to give ADH, but this has a short half-life, so an analogue desmopressin is given instead.
What is the unusual management of central diabetes insipidus?
Use thiazide diuretics
This could protect against hypernatremia.
Encourage proximal tubule water reabsorption.
And increase aquaporin expression.
What is nephrogenic diabetes insipidus?
Lack of sensitivity to ADH.
Caused by genetics, hypercalcaemia (high Ca2+), or toxicity to Lithium.
What is the management of nephrogenic diabetes insipidus?
Thiazide diuretic - as have hypernatremia (high Na+), so get rid of extra Na+, and the ratio of Na+ to water is ok, despite water being lost.
Diuretics inhibit Na+ reabsorption by Na+/Cl- cotransporter (NCC), causes Na+ loss, so Na+ and water are lost in proportion.
Coupled with low salt diet to combat hypernatremia.
How does diabetes mellitus cause polyuria?
There is an increase in glucose concentration, so glucose hits the transport maximum, and cannot be reabsorbed.
Glucose stays in the filtrate, so there is high glucose concentration and high urine output.
What is SIADH?
Syndrome in inappropriate ADH.
Too much ADH, so kidneys retain volume when it shouldn’t - causes volume overload.
They produce concentrated urine, so there is low Na+ - hyponatremia.
Caused by head injury and major trauma of being unwell.
What is the treatment for SIADH?
Fluid restriction, and give urea - to regulate urea secretion, and act as an osmotic diuretic - urea stays in filtrate, so water stays in filtrate, and water leaves the body in the urine.
Vaptan class of drugs which are V2 receptor antagonists, this blocks the receptors so there is less sensitivity of the kidney to ADH.
What is the effect of osmolality on thirst?
Inadequate water intake increases osmolality of plasma.
Osmolality is detected in the AV3V region.
The AV3V neurones project to the median preoptic area of the hypothalamus to increase thirst.
What happens when we drink salt water?
Salt water has very high osmolality, much higher than the maximum osmolality that kidneys can produce.
Take in solute molecules, to get rid of these additional ions, must go through kidneys, but as they are secreted it adds osmolality to the kidneys, which keeps water in the filtrate.
So 1.4Kg of water needs drinking for every kg of salt water.
What osmolality is ADH secreted at?
If osmolality falls to 280, hypothalamus switches off secretion of ADH.
If above 280, secretes ADH.
So can tightly regulate osmolality in a narrow range.
By regulating ADH, can cause urine output to range from very small volumes 0.1L to 24L.
What are the forms of osmolytes?
Carbohydrates, fat proteins, with Na+ and Cl- the most dominant.
All these intakes reach the circulation from the gut in a water-soluble form, and so contribute osmolytes which affect osmolality.
What happens to carbohydrates after absorption?
Carbohydrates are converted into simple sugars, and transported into cells, so don’t contribute much to osmolality, except in diabetes mellitus.
Glucose is oxidised to CO2, which is rapidly excreted, and water, so only briefly increase osmolality.
What happens to proteins after absorption?
Proteins are broken down into amino acids, which enter cells, so plasma change in osmolality is small.
Nitrogen can be removed by urea, which has high renal clearance, so contribution to osmolality is low.
What is HSS?
Hyperosmolar hyperglycaemic state:
In diabetes mellitus, glucose concentration is so high that contributes largely to osmolality.
Hyperosmolality gives strong thirst, if insufficient, leads to cellular dehydration, leads to hyponatremia.
Causes seizures and increased blood viscosity.
