RENAL - Endocrine Control of Body Fluid Volume

Question 1

Describe body fluid distribution.

Answer 1

• 65% intracellular (cytoplasm)
• 25% interstitial fluid
• 7% - in circulation as plasma
• <1% as CSF
• 55% of TBW in a 70 kg male is water - varies depending on sex, age and weight

Question 2

What happens when ECF increased by 20 - 30%?

Answer 2

• Buffered by increase in blood volume (up to a limit because strain on heart)
• Excess fluid leaks into interstitial space

Question 3

What happens when ECF increased by 30-50%?

Answer 3

• Blood volume no longer increased
• Tissues become more compliant
• Greater fluid in interstitial space - oedema

Question 4

How does the body maintain normal volume homeostasis?

Answer 4

• Detect volume changes
• Eliminate excess water or increase water intake

Question 5

(a) What is the formula for blood pressure?

(b) What is the formula for cardiac output?

(c) What is the formula for stroke volume?

(d) Using this what would be the consequences of increasing plasma volume?

Answer 5

• Cardiac output x TPR
• Heart rate x stroke volume
• EDV - ESV (both of which are directly proportional to extracellular volume)
• Increase in stroke volume so increase in cardiac output and BP

Question 6

(a) What are plasma, interstitial and intracellular osmolarity?

(b) What happens when extracellular osmolarity increases and what can cause this?

(c) What happens when extracellular osmolarity decreases?

Answer 6

• 300 mOsm
• Water drawn out of cells causing cell shrinkage - due to decrease in water content/increase in sodium content
• Water enters cells down osmotic gradient and causes cells to swell

Question 7

Describe the neurons involved in sensing changes in plasma osmolarity. PART 1

Answer 7

• Neurons lie in subfornical organ and OVLT - both are considered CVOs
• CVOs lack a blood brain barrier that would make brain impermeable to substances in peripheral circulation - can sample from circulation
• Have specialised receptors on membrane - through these, sodium increase can trigger action potentials

Question 8

Describe the neurons involved in sensing changes in plasma osmolarity. PART 2

Answer 8

• Increased osmolarity accompanying increase in relative amount of sodium draws water out of cells via osmosis
• Cell shrinkage - detected causing triggering of action potentials
• Cells have AngII receptors - which can also trigger action potentials
• Neurons are sensitive to peripheral baroreceptor activation - triggered by reductions in blood volume or pressure

Question 9

What usually happens in plasma by reducing total amount of water?

Answer 9

Relative amount of sodium in blood is increased

Question 10

Describe peripheral osmoception

Answer 10

• Has been suggested these receptors more susceptible to hypo-osmolarity and respond in response to drinking water
• Decrease in plasma osmolarity occurring after drinking detected to to avoid over-drinking and further osmolarity decreases
• Plasma osmolarity in liver transplant patients is higher than normal - in denervation of hepatic portal vein afferents
• Afferents found near hepatic portal vein

Question 11

What is the effect of detection of an increase in plasma osmolarity?

Answer 11

• Stimulation of insula cortex and cingulate cortex
• Activates behavioural drive for thirst

Question 12

Describe ADH formation and what stimulates its release.

Answer 12

• Released in response to increase in osmolarity - from posterior pituitary
• Synthesised in PVN and SON in hypothalamus and transported to posterior pituitary for secretion into systemic circulation

Question 13

RECAP - What happens as filtrate passes along the nephron?

Answer 13

• Water and sodium and other solutes reabsorbed
• When filtrate reaches descending Loop, osmolarity of filtrate is 300 mOsm (isosmotic with plasma/interstitium)
• NaCl leaving via ascending limb creates concentration gradient driving water reabsorption from descending limb

Question 14

(a) Are DCT cells and principle cells of the collecting duct permeable to water?

(b) What receptors are found on the basolateral side of these cells?

(c) What are the effects of aquaporin insertion?

Answer 14

• No
• ADH receptors - stimulates aquaporin insertion into apical membranes
• Osmolarity of filtrate entering near this area can be as low as 100 mOsm and osmolarity of ICF is 300 mOsm, aquaporin insertion leads to movement of water down concentration gradient into cell

Question 15

Describe the behaviour of water near the basolateral side of principle cells in collecting duct and DCT cells.

Answer 15

• Cells are always water permeable - due to expression of non ADH-regulated aquaporins
• Concentration outside of this part of nephron, in particular collecting duct parallel to Loop of Henle, can be as high as 1200 mOsm (due to concentration gradient established by Loop of Henle)
• Water flows freely through basolateral side of cell and into circulation

Question 16

(a) What is nephrogenic diabetes insipidus?

(b) What is a common cause of acquired nephrogenic diabetes insipidus?

(c) Describe central diabetes insipidus.

Answer 16

• Kidney insensitive to effects of ADH or mutation in aquaporin gene making it non-functional. DCT cells and collecting duct cannot insert aquaporins into apical membrane. Reduced water reabsorption - increased urination
• Lithium poisoning - prevent signalling mechanism leading to ADH binding to its receptor - so reduced aquaporin expression
• Hypothalamus and/or pituitary gland don’t secrete enough ADH - normally as a result of head injury or brain tumour

Question 17

Describe macula densa cells.

Answer 17

• Found in DCT - respond to low sodium in filtrate
• Juxtaglomerular cells (specialised endothelial cells of afferent and efferent arterioles) respond to signals from macula densa - as well as sympathetic stimulatiion and changes in renal pressure (caused by renin)

Question 18

Describe the basic steps of RAAS.

Answer 18

• In response to low sodium , low blood volume (detected by atrial volume receptors and subsequent excitation of sympathetic nerves or directly by low blood flow to kidneys) or low blood pressure, JG cells secrete renin into bloodstream
• Angiotensinogen produced by liver
• Renin cleaves angiotensinogen to angiotensin I
• Converted to AngII by ACE - in capillaries of lung
• Promotes aldosterone release

Question 19

Describe the effects of carotid and arterial baroreceptors, and atrial volume receptors.

Answer 19

• Low blood pressure or low blood volume are detected by carotid and arterial baroreceptors and atrial volume receptors respectively.
• Carotid baroreceptors, located at the carotid bifurcation, sense changes in pulse pressure
• Intensity of each pulse (as measure of pulse pressure and arterial pressure) - relayed to brain as action potentials - the higher the blood pressure, the higher the frequency of action potentials

Question 20

What nerves are the action potentials from the carotid and aortic baroreceptors, and atrial volume receptors relayed through?

Answer 20

• For carotid baroreceptors this is relayed for the glossopharyngeal nerve (cranial nerve IX).
• For aortic baroreceptors and atrial volume receptors this is relayed via the vagus nerve (cranial nerve X)

Question 21

Describe the nervous aspect of RAAS.

Answer 21

• Information relayed to brainstem and then to hypothalamus
• Hypothalamus can control activity of renal sympathetic nerves - if baroreceptors detect BP decrease, increase in renal sympathetic nerve activity
• These nerves innervate JG cells - stimulate renin release
• JG cells are pressure sensitive - respond to changes in renal perfusion pressure.
• Decrease in this pressure leads to renin secretion

Question 22

Why does a decrease in sodium in the DCT lead to increased RAAS activity? PART 1

Answer 22

• Kidney maintains GFR within narrow range
• If systemic BP decreases, RBF decreases - GFR decreases
• Reduced rate of transport of filtrate through nephron
• Decreased velocity of fluid flow leads to increase in sodium reabsorption - more time for reabsorption
• Reduced concentration at DCT

Question 23

Why does a decrease in sodium in the DCT lead to increased RAAS activity? PART 2

Answer 23

• This would be detected by macula densa cells
• AngII directly stimulates increase in sodium reabsorption from PCT
• Increased expression of sodium-hydrogen antiporter, sodium-potassium ATPase and sodium-bicarbonate co-transporter

Question 24

AngII stimulates secretion of aldosterone from adrenal cortex. What are the effects of this? PART 1

Answer 24

• Acts on DCT and principle cells of collecting duct - increased sodium reabsorption
• Steroid hormone - intracellular so moves across membrane
• Binding to mineralcorticoid receptor increases gene transcription
• Greater expression of ENaC increased on apical membrane

Question 25

AngII stimulates secretion of aldosterone from adrenal cortex. What are the effects of this? PART 2

Answer 25

• ENaCs already present phosphorylated - increased permeability and prevent degradation
• Increase in expression of sodium- potassium ATPase and apical membrane potassium channels
• Low intracellular sodium concentration - sodium moves from lumen into cell down concentration gradient
• Sodium-potassium ATPase pushes sodium out of basolateral membrane in exchange for potassium

Question 26

AngII stimulates secretion of aldosterone from adrenal cortex. What are the effects of this? PART 3

Answer 26

• Due to the influx of positively charged sodium from the lumen, the filtrate is slightly electronegative compared to the inside of the cell, which draws potassium out
• This is why conditions which increase aldosterone secretion (e.g. Conn’s syndrome) usually present with hypokalaemia
• Remember also that these cells are responding to ADH as well, so they will likely contain aquaporins. The presence of ENaCs and the subsequent increase in intracellular osmolarity will drive water into the cell through osmosis – hence water and sodium reabsorption are closely linked.

Question 27

Describe the pharmacological importance of ENaC channels.

Answer 27

• Amiloride - antihypertensive drug - blocks ENaC channel - prevents sodium influx from filtrate. By blocking sodium reabsorption, water reabsorption reduced - leading to diuresis
• Blocking sodium reabsorption also prevents the filtrate from becoming electronegative, potassium is not lost, thus this class of diuretics are known as potassium-sparing diuretics

Question 28

Describe pressure natriuresis.

Answer 28

• Decrease in systemic BP leads to increase in RAAS activity
• AngII preferentially constricts efferent arteriole - increase in GFR and decrease in blood flow to peri-tubular capillaries
• If AngII were to decrease, opposite happens i.e efferent arteriole dilated and increased flow to capillaries
• Increased blood flow increases hydrostatic pressure in peri-tubular capillaries - reduces sodium and water reabsorption
• The decrease in AngII also decreases the effects of AngII on sodium reabsorption in the proximal convoluted tubule, leading to natriuresis

Question 29

Describe ANP. PART 1

Answer 29

• Released from cardiomyocytes in atria of heart in response to increased distension
• Decreases blood volume and venous return
• Dilation of afferent arteriole and constriction of efferent arteriole - increased in hydrostatic pressure of glomerulus leading to increase in GFR

Question 30

Describe ANP. PART 2

Answer 30

• Opposes actions of AngII in PCT by blocking sodium-hydrogen antiporter - prevents sodium reabsorption
• Increase in diuresis and natriuresis - decrease in extracellular volume